Substituted 2-anilinopryimidines useful as protein kinase inhibitors

ABSTRACT

Compounds of formula (1) are described: ##STR1## and the salts, solvates, hydrates and N-oxides thereof, in which R 1 , R 2 , R 3 , R 4 , R 5 , R 6  and R 7  have the meanings given in claim 1. The compounds are selective inhibitors of protein kinases, especially src-family protein kinases and are of use in the prophylaxis and treatment of immune diseases, hyperproliferative disorders and other diseases in which inappropriate protein kinase action is believed to have a role.

This invention relates to substituted 2-anilinopyrimidines, to processesfor their preparation, to pharmaceutical compositions containing them,and to their use in medicine.

Protein kinases participate in the signalling events which control theactivation, growth and differentiation of cells in response toextracellular mediators and to changes in the environment. In general,these kinases fall into two groups; those which preferentiallyphosphorylate serine and/or threonine residues and those whichpreferentially phosphorylate tyrosine residues [Hanks, S K, Hunter T,FASEB. J. 9, 576-596 (1995)]. The serine/threonine kinases include forexample, protein kinase C isoforms [Newton A C, J. Biol. Chem. 270,28495-28498 (1995)] and a group of cyclin-dependent kinases such as cdc2[Pines J, Trends in Biochemical Sciences 18, 195-197 (1995)]. Thetyrosine kinases include membrane-spanning growth factor receptors suchas the epidermal growth factor receptor [Iwashita S and Kobayashi M.Cellular Signalling 4, 123-132 (1992)], and cytosolic non-receptorkinases such as ZAP-70 and csk kinases [Chan C et al Ann. Rev. Immunol.12, 555-592 (1994)]. A particular group of non-receptor tyrosine kinasesare a group known as the src family which includes p56^(lck) andp59^(fyn) [Kefelas P et al International Journal of Biochemistry andCell Biology 27, 551-563 (1995)].

Inappropriately high protein kinase activity has been implicated in manydiseases resulting from abnormal cellular function. This might ariseeither directly or indirectly, for example by failure of the propercontrol mechanisms for the kinase, related for example to mutation,over-expression or inappropriate activation of the enzyme; or by over-or underproduction of cytokines or growth factors also participating inthe transduction of signal upstream or downstream of the kinase. In allof these instances, selective inhibition of the action of the kinasemight be expected to have a beneficial effect.

We have now found a series of substituted 2-anilinopyrimidines which arepotent and selective inhibitors of protein kinases, especiallysrc-family protein kinases. The compounds are thus of use in theprophylaxis and treatment of immune diseases, hyperproliferativedisorders and other diseases in which inappropriate protein kinaseaction is believed to have a role.

Thus, according to one aspect of the invention, we provide a compound offormula (1): ##STR2## wherein R¹ is a --XR⁸ group [where X is a covalentbond, --O--, --S--, --C(O)--, --C(S)--, --C(O)O--, --S(O)--, --S(O₂)--,--CH₂ --, -or N(R⁹)--[where R⁹ is a hydrogen atom or a straight orbranched alkyl group] and R⁸ is a hydrogen atom or an optionallysubstituted aliphatic, cycloaliphatic, heteroaliphatic,heterocycloaliphatic, aromatic or heteroaromatic group], or a --NO₂,--CN, --SO₂ NH₂, --SO₂ NHR⁸, --SO₂ N(R⁸)₂ [where each R⁸ group may bethe same or different], --CONH₂, --CONHR⁸, --CON(R⁸)₂ [where each R⁸group may be the same or different], --CSNH₂, --CSNHR⁸, --CSN(R⁸)₂[where each R⁸ group may be the same or different], --NH₂ or substitutedamino group;

R² and R³ which may be the same or different is each a hydrogen orhalogen atom or a group selected from an optionally substitutedaliphatic, cycloaliphatic, heteroaliphatic, heterocycloaliphatic, --OH,--OR¹⁰ [where R¹⁰ is an optionally substituted aliphatic group],--OR^(10a) [where R^(10a) is an optionally substituted cycloaliphatic,heteroaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group]--SH, --NO₂, --CN, --SR⁸, --COR⁸, S(O)R⁸, --SO₂ R⁸, --SO₂ NH₂, --SO₂NHR⁸, --SO₂ N(R⁸)₂ [where each R⁸ group may be the same or different]--CO₂ H, --CO₂ R⁸, --CONH₂, --CONHR⁸, --CON(R⁸)₂, [where each R⁸ groupmay be the same or different] --CSNH₂, --CSNHR⁸, --CSN(R⁸)₂, [where eachR⁸ group may be the same or different] --NH₂ or substituted amino groupprovided that when one or both of R² and R³ is an --OR¹⁰ group then R¹is an --OR⁸ group in which R⁸ is an optionally substitutedcycloaliphatic, heteroaliphatic, heterocycloaliphatic, aromatic orheteroaromatic group or an aliphatic group substituted by a cyclic aminogroup;

R⁴ is a hydrogen atom or a straight or branched alkyl group;

R⁵ is a hydrogen atom or an optionally substituted straight or branchedalkyl, alkenyl or alkynyl group;

R⁶ is a hydrogen or halogen atom or an amino, substituted amino, nitro,--CO₂ H, or --CO₂ R⁸ group or a group --X¹ --R^(6a) where X¹ is a directbond or a linker atom or group and R^(6a) is an optionally substitutedstraight or branched alkyl, alkenyl or alkynyl group;

R⁷ is an optionally substituted aliphatic, cycloaliphatic,heteroaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group;and the salts, solvates, hydrates and N-oxides thereof.

When in the compounds of formula (1) X¹ is present as a linker atom orgroup it may be for example an --O-- or --S-- atom or a --C(O)--,--C(S)--, --S(O)--, --S(O)₂ --, --N(R¹¹)-- [where R¹¹ is a hydrogen atomor a C₁₋₆ alkyl, e.g. methyl or ethyl, group], --CON(R¹¹)--,--OC(O)N(R¹¹ --, --CSN(R¹¹)--, --N(R¹¹)CO--, --N(R¹¹)C(O)O--,--N(R¹¹)CS--, --SON(R¹¹), --SO₂ N(R¹¹), --N(R¹¹)SO₂ --,--N(R¹¹)CON(R¹¹)--, --N(R¹¹)CSN(R¹¹)--, --N(R¹¹)SON(R¹¹)-- or--N(R¹¹)SO₂ N(R¹¹) group.

In the compounds of formula (1), when R¹ is --XR⁸ and R⁸ is anoptionally substituted aliphatic group, R⁸ may be an optionallysubstituted C₁₋₁₀ aliphatic group for example an optionally substitutedstraight or branched chain C₁₋₆ alkyl, e.g. C₁₋₃ alkyl, C₂₋₆ alkenyl,e.g. C₂₋₄ alkenyl, or C₂₋₆ alkynyl, e.g. C₂₋₄ alkynyl group. Each ofsaid groups may be optionally interrupted by one or two heteroatoms orheteroatom-containing groups represented by X² [where X² is an atom orgroup as just described for X¹ ], to form an optionally substituted R⁸heteroaliphatic group.

Particular examples of aliphatic groups represented by R⁸ includeoptionally substituted --CH₃, --CH₂ CH₃, --(CH₂)₂ CH₃, --CH(CH₃ )₂,--(CH₂)₃ CH₃, --CH(CH₃)CH₂ CH₃, --CH₂ CH(CH₃)₂, --C(CH₃)₃, --(CH₂)₄ CH₃,--(CH₂)₅ CH₃, --CHCH₂, --CHCHCH₃, --CH₂ CHCH₂, --CHCHCH₂ CH₃, --CH₂CHCHCH₃, --(CH₂)₂ CHCH₂, --CCH, --CCCH₃, --CH₂ CCH, --CCCH₂ CH₃, --CH₂CCCH₃, or --(CH₂)₂ CCH groups. Where appropriate each of said groups maybe optionally interrupted by one or two atoms and/or groups X² to forman optionally substituted heteroaliphatic group. Particular examplesinclude --CH₂ X² CH₃, --CH₂ X² CH₂ CH₃, --(CH₂)₂ X² CH₃ and --(CH₂)₂ X²CH₂ CH₃ groups.

The optional substituents which may be present on these aliphatic and/orheteroaliphatic groups include one, two, three or more substituentsselected from halogen atoms, e.g. fluorine, chlorine, bromine or iodineatoms, or hydroxyl, C₁₋₆ alkoxy, e.g. methoxy or ethoxy, thiol, C₁₋₆alkylthio e.g. methylthio or ethylthio, --SC(NH)NH₂, --CH₂ C(NH)NH₂,amino, substituted amino or cyclic amino groups.

Substituted amino groups include for example groups of formulae --NR⁹R¹⁰ [where R⁹ is an optionally substituted C₁₋₆ alkyl, C₂₋₆ alkenyl orC₂₋₆ alkynyl group optionally interrupted by one or two heteroatoms orheteroatom-containing groups represented by X³ (where X³ is an atom orgroup as described above for X¹) and R¹⁰ is a hydrogen atom or is agroup as just defined for R⁹ ], --N(R¹⁰)COR⁹, --N(R¹⁰)CSR⁹,--N(R¹⁰)SOR⁹, --N(R¹⁰)SO₂ R⁹, --N(R¹⁰)CONH₂, --N(R¹⁰)CONR⁹ R¹⁰,--N(R¹⁰)C(O)OR⁹, --N(R¹⁰)C(NH)NH₂, --N(R¹⁰)C(NH)NR⁹ R¹⁰, --N(R¹⁰)CSNH₂,--N(R¹⁰)CSNR⁹ R¹⁰, --N(R¹⁰)SONH₂, --N(R¹⁰)SONR⁹ R¹⁰, --N(R¹⁰)SONH₂,--N(R¹⁰)SO₂ NH₂, --N(R¹⁰)SO₂ NR⁹ R¹⁰, or --N(R¹⁰)Cyc¹ [where Cyc¹ is anoptionally substituted C₃₋₇ monocyclic carbocyclic group optionallycontaining one or more --O-- or --S-- atoms or --N(R¹¹)--, --C(O)--,--C(S)--, --S(O)-- or --S(O₂)-- groups].

Cyclic amino substituents which may be present on R⁸ aliphatic orheteroaliphatic groups include groups of formula --NHet¹, where --NHet¹is an optionally substituted C₃₋₇ cyclic amino group optionallycontaining one or more other heteroatoms or heteroatom containing groupsselected from --O-- or --S-- atoms --N(R¹¹)--, --C(O), --C(S)--,--S(O)-- or --S(O₂)-- groups.

Particular examples of amino, substituted amino and cyclic amino groupsinclude --NH₂, methylamino, ethylamino, dimethylamino, diethylamino,--NHCyc¹ where Cyc¹ is an optionally substituted cyclopentyl,cyclohexyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl,morpholinyl, piperazinyl or thiomorpholinyl group, or --NHet¹ where--NHet¹ is an optionally substituted pyrrolidinyl, imidazolidinyl,pyrazolidinyl, piperidinyl, morpholinyl, piperazinyl or thiomorpholinylgroup. Optional substituents which may be present on these groups andsubstituted and cyclic amino groups in general include one, two or threehalogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms, or C₁₋₄alkyl, e.g. methyl or ethyl, hydroxyl, or C₁₋₄ alkoxy, e.g. methoxy orethoxy groups.

When R⁸ is present in compounds of formula (1) as an optionallysubstituted cycloaliphatic group it may be an optionally substitutedC₃₋₁₀ cycloaliphatic group. Particular examples include optionallysubstituted C₃₋₁₀ cycloalkyl, e.g. C₃₋₇ cycloalkyl, or C₃₋₁₀cycloalkenyl e.g. C₃₋₇ cycloalkenyl groups.

Heteroaliphatic or heterocycloaliphatic groups represented by R⁸ includethe aliphatic or cycloaliphatic groups just described for R⁸ but witheach group additionally containing one, two, three or four heteroatomsor heteroatom-containing groups represented by X², where X² is asdescribed above.

Particular examples of R⁸ cycloaliphatic and heterocycloaliphatic groupsinclude optionally substituted cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, 2-cyclobuten-1-yl, 2-cyclopenten-1-yl,3-cyclopenten-1-yl, 2,4-cyclopentadien-1-yl, 3,5,-cyclohexadien-1-yl,tetrahydrofuranyl, pyrroline, e.g. 2- or 3-pyrrolinyl, pyrrolidinyl,dioxolanyl, e.g. 1,3-dioxolanyl, imidazolinyl, e.g. 2-imidazolinyl,imidazolidinyl, pyrazolinyl, e.g. 2-pyrazolinyl, pyrazolidinyl, pyranyl,e.g. 2- or 4-pyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl,1,4-dithianyl, thiomorpholinyl, piperazinyl, 1,3,5-trithianyl, oxazinyl,e.g. 2H-1,3-, 6H-1,3-, 6H-1,2-, 2H-1,2- or 4H-1,4-oxazinyl,1,2,5-oxathiazinyl, isoxazinyl, oxathiazinyl, e.g. 1,2,5 or1,2,6-oxathiazinyl, or 1,3,5-oxadiazinyl groups.

Optional substituents which may be present on R⁸ cycloaliphatic andheterocycloaliphatic groups include those optional substituentsdescribed above for R⁸ when it is an aliphatic group. Theheterocycloaliphatic groups may be attached to the remainder of themolecule of formula (1) through any appropriate ring carbon orheteroatom.

When R⁸ is present as an aromatic group in compounds of formula (1) itmay be for example an optionally substituted monocyclic or bicyclicfused ring C₆₋₁₂ aromatic group, such as an optionally substitutedphenyl, 1- or 2-naphthyl, 1- or 2-tetrahydronaphthyl, indanyl or indenylgroup.

Heteroaromatic groups represented by R⁸ include optionally substitutedC₁₋₉ heteroaromatic groups containing for example one, two, three orfour heteroatoms selected from oxygen, sulphur or nitrogen atoms. Ingeneral, the heteroaromatic groups may be for example monocyclic orbicyclic fused ring heteroaromatic groups. Monocyclic heteroaromaticgroups include for example five- or six-membered heteroaromatic groupscontaining one, two, three or four heteroatoms selected from oxygen,sulphur or nitrogen atoms. Bicyclic heteroaromatic groups include forexample nine- to thirteen-membered fused-ring heteroaromatic groupscontaining one, two or more heteroatoms selected from oxygen, sulphur ornitrogen atoms.

Examples of heteroaromatic groups represented by R⁸ include optionallysubstituted pyrrolyl, furyl, thienyl, imidazolyl, N-methylimidazolyl,N-ethylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,1,3,4-thiadiazole, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl,1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, benzofuryl,[2,3-dihydro]benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl,isobenzothienyl, indolyl, isoindolyl, benzimidazolyl,imidazo[1,2-a]pyridyl, benzothiazolyl, benzoxazolyl, benzopyranyl,[3,4-dihydro]benzopyranyl, quinazolinyl, naphthyridinyl,pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl,quinolinyl, isoquinolinyl, tetrazolyl, 5,6,7,8-tetrahydroquinolinyl,5,6,7,8-tetrahydroisoquinolinyl, and imidyl, e.g. succinimidyl,phthalimidyl, or naphthalimidyl such as 1,8-naphthalimidyl.

Optional substituents which may be present on any of the above aromaticor heteroaromatic groups in compounds of formula (1) include one, two,three or more substituents, each represented by the group R¹². Thesubstituent R¹² may be selected from an atom or group R¹³ or-Alk(R¹³)_(m), where R¹³ is a halogen atom, or an amino (--NH₂), --NHR¹⁴[where R¹⁴ is an -Alk(R¹³)_(m), heterocycloalkyl, -Alk-heterocycloalkyl,aryl or heteroaryl group], --N(R¹⁴)₂ [where each R¹⁴ group is the sameor different], nitro, cyano, hydroxyl (--OH), --OR¹⁴, formyl, carboxyl(--CO₂ H), esterified carboxyl, thiol (--SH), --SR¹⁴, --COR¹⁴, --CSR¹⁴,--SO₃ H, --SO₂ R¹⁴, --SO₂ NH₂, --SO₂ NHR¹⁴, SO₂ N[R¹⁴ ]₂, --CONH₂,--CSNH₂, --CONHR¹⁴, --CSNHR¹⁴, --CON[R¹⁴ ]₂, --CSN[R¹⁴ ]₂, --N(R¹¹)SO₂ H[where R¹¹ is as defined above], --N(R¹¹)SO₂ R¹⁴, --N[SO₂ R¹⁴ ]₂,--N(R¹¹)SO₂ NH₂, --N(R¹¹)SO₂ NHR¹⁴, --N(R¹¹)SO₂ N[R¹⁴ ]₂, --N(R¹¹)COR¹⁴,--N(R¹¹)CONH₂, --N(R¹¹)CONHR¹⁴, --N(R¹¹)CON[R¹⁴ ]₂, --N(R¹¹)CSR¹⁴,--N(R¹¹)CSNH₂, --N(R¹¹)CSNHR¹⁴, --N(R¹¹)CSN[R¹⁴ ]₂, --N(R¹¹)C(O)OR¹⁴, oran optionally substituted cycloalkyl, aryl or heteroaryl group; Alk is astraight or branched C₁₋₆ alkylene, C₂₋₆ alkenylene or C₂₋₆ alkynylenechain, optionally interrupted by one, two or three --O-- or --S-- atomsor S--(O)--, --S(O)₂ -- or --N(R¹¹)-- groups; and m is zero or aninteger 1, 2 or 3.

When in the group -Alk(R¹³)_(m) m is an integer 1, 2 or 3, it is to beunderstood that the substituent or substituents R¹³ may be present onany suitable carbon atom in -Alk. Where more than one R¹³ substituent ispresent these may be the same or different and may be present on thesame or different atom in -Alk or in R⁷ as appropriate. Thus forexample, R⁷ may represent a --CH(R¹³)₂ group, such as a --CH(OH)Ar groupwhere Ar is an aryl or heteroaryl group as defined below. Clearly, whenm is zero and no substituent R¹³ is present the alkylene, alkenylene oralkynylene chain represented by Alk becomes an alkyl, alkenyl or alkynylgroup.

When R¹³ is a halogen atom it may be for example a fluorine, chlorine,bromine, or iodine atom.

Esterified carboxyl groups represented by the group R¹³ include groupsof formula --CO₂ Alk¹ wherein Alk¹ is a straight or branched, optionallysubstituted C₁₋₈ alkyl group such as a methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl, s-butyl or t-butyl group; a C₆₋₁₂ arylC₁₋₈alkyl group such as an optionally substituted benzyl, phenylethyl,phenylpropyl, 1-naphthylmethyl or 2-naphthylmethyl group; a C₆₋₁₂ arylgroup such as an optionally substituted phenyl, 1-naphthyl or 2-naphthylgroup; a C₆₋₁₂ aryloxyC₁₋₈ alkyl group such as an optionally substitutedphenyloxymethyl, phenyloxyethyl, 1-naphthyloxymethyl, or2-naphthyloxymethyl group; an optionally substituted C₁₋₈alkanoyloxyC₁₋₈ alkyl group, such as a pivaloyloxymethyl,propionyloxyethyl or propionyloxypropyl group; or a C₆₋₁₂ aroyloxyC₁₋₈alkyl group such as an optionally substituted benzoyloxyethyl orbenzoyloxypropyl group. Optional substituents present on the Alk¹ groupinclude R¹³ substituents described above.

When Alk is present in or as a substituent R¹² it may be for example amethylene, ethylene, n-propylene, i-propylene, n-butylene, i-butylene,s-butylene, t-butylene, ethenylene, 2-propenylene, 2-butenylene,3-butenylene, ethynylene, 2-propynylene, 2-butynylene or 3-butynylenechain, optionally interrupted by one, two, or three --O-- or --S--,atoms or --S(O)--, --S(O)₂ -- or --N(R¹¹)-- groups.

Optionally substituted cycloalkyl groups represented by the group R¹³include optionally substituted C₅₋₇ cycloalkyl groups such as optionallysubstituted cyclopentyl or cyclohexyl groups.

Heterocycloalkyl groups represented by the group R¹² or R¹⁴ includeoptionally substituted heteroC₃₋₆ cycloalkyl groups containing one ortwo oxygen, sulphur or nitrogen atoms. Particular examples of suchgroups include optionally substituted azetidinyl pyrrolidinyl,piperidinyl, piperazinyl, homopiperazinyl, morpholinyl orthiomorpholinyl groups. The heterocycloalkyl group may be attached tothe remainder of the molecule through any of its ring carbon atoms, orwhere present, ring nitrogen atom. Where the group R¹² is an-Alk-heterocycloalkyl group, Alk may be as defined above and theheterocycloalkyl portion may be as just defined, attached to Alk throughany of its ring carbon atoms, or where present, ring nitrogen atom.

Optional substituents which may be present on R¹², R¹³ or R¹⁴ cycloalkylor heterocycloalkyl groups include one or two C₁₋₆ alkyl, e.g. methyl orethyl, hydroxyl (--OH) hydroxyC₁₋₆ alkyl, e.g. hydroxymethyl orhydroxyethyl, or C₁₋₆ alkoxy, e.g. methoxy or ethoxy groups. Thesubstituent(s) may be present on any available ring carbon or nitrogenatom as appropriate.

Aryl and heteroaryl groups represented by the groups R¹³ or R¹⁴ includefor example optionally substituted monocyclic or bicyclic C₆ ₁₋₁₂aromatic groups, or C₁₋₉ heteroaromatic groups such as those describedabove in relation to the group R⁸.

Particularly useful atoms or groups represented by R¹² include fluorine,chlorine, bromine or iodine atoms, or C₁₋₆ alkyl, C₁₋₆ alkylamino, C₁₋₆hydroxyalkyl, C₁₋₆ alkylthiol, C₁₋₆ alkoxy, hydroxyC₁₋₆ alkoxy,aminoC₁₋₆ alkoxy, C₁₋₆ alkylaminoC₁₋₆ alkoxy, C₁₋₆ dialkylaminoC₁₋₆alkoxy, optionally substituted C₅₋₇ cyclo-alkoxy, optionally substitutedC₅₋₇ cycloalkyl, optionally substituted C₅₋₇ cycloalkylamino, haloC₁₋₆alkyl, haloC₁₋₆ alkoxy, C₁₋₆ alkylamino, amino (--NH₂), aminoC₁₋₆ alkyl,C₁₋₆ dialkylamino, hydroxyC₁₋₆ alkylamino, aminoC₁₋₆ alkylamino, C₁₋₆alkylaminoC₁₋₆ alkylamino, C₁₋₆ dialkylaminoC₁₋₆ alkylamino, C₁₋₆alkylaminoC₁₋₆ dialkylamino, C₁₋₆ dialkylaminoC₁₋₆ dialkylamino, nitro,cyano, hydroxyl (--OH), formyl [HC(O)--], carboxyl (--CO₂ H), --CH₂ CO₂H, --OCH₂ CO₂ H, --CO₂ Alk¹ [where Alk¹ is as defined above], --CH₂ CO₂Alk¹, C₁₋₆ alkoxycarbonylC₁₋₆ alkoxy, C₁₋₆ alkanoyl, optionallysubstituted phenyl C₁₋₆ alkanoyl, thiol (--SH), thioC₁₋₆ alkyl,--SC(NH)NH₂, sulphonyl (--SO₃ H), C₁₋₆ alkylsulphonyl, optionallysubstituted phenylsulphonyl, aminosulphonyl (--SO₂ NH₂), C₁₋₆alkylaminosulphonyl, C₁₋₆ dialkylaminosulphonyl, optionally substitutedphenylamino-sulphonyl, carboxamido (--CONH₂), C₁₋₆ alkyl-aminocarbonyl,C₁₋₆ dialkylaminocarbonyl, optionally substituted phenyl-aminocarbonyl,aminocarbonylmethyl, C₁₋₆ alkylaminocarbonylmethyl, optionallysubstituted benzylaminocarbonylmethyl, --NHC(S)NH₂, sulphonyl-amino(--NHSO₂ H), C₁₋₆ alkylsulphonylamino, C₁₋₆ dialkylsulphonylamino,optionally substituted phenylsulphonylamino, aminosulphonylamino(--NHSO₂ NH₂), C₁₋₆ alkylaminosulphonylamino, C₁₋₆dialkylaminosulphonylamino, optionally substitutedphenylaminosulphonylamino, aminocarbonyl-amino, C₁₋₆alkylaminocarbonylamino C₁₋₆ dialkylaminocarbonylamino,phenylaminocarbonylamino, C₁₋₆ alkanoylamino, aminoC₁₋₆ alkanoylamino,optionally substituted pyridylcarboxyamino, C₁₋₆ alkanoylaminoC₁₋₆alkyl, C₁₋₆ alkoxycarbonylamino, optionally substituted heteroC₃₋₆cycloalkyl, piperidinyl, piperazinyl, 4-methylpiperazinyl,homopipeprazinyl, or morpholinyl, optionally substituted heteroC₃₋₆cycloalkylC₁₋₆ alkyl, piperidinylC₁₋₆ alkyl, piperazinylC₁₋₆ alkyl ormorpholinylC₁₋₆ alkyl, optionally substituted heteroC₃ ₁₋₆ alkylC₁₋₆alkylamino, optionally substituted heteroC₃₋₆ cycloalkylamino,tetrazolyl, optionally substituted phenylamino, optionally substitutedbenzylamino, optionally substituted benzyloxy, or optionally substitutedpyridiylmethylamino group.

Where desired, two R¹² substituents may be linked together to form acyclic group such as a cyclic ether, e.g. a C₁₋₆ alkylenedioxy groupsuch as a methylenedioxy or ethylenedioxy group.

Especially useful R¹² substituents include for example fluorine,chlorine, bromine or iodine atoms, or a methylamino, ethylamino,hydroxymethyl, hydroxyethyl, methylthiol, ethylthiol, methoxy, ethoxy,n-propoxy, 2-hydroxyethoxy, 3-hydroxypropoxy, 4-hydroxybutoxy,2-aminoethoxy, 3-aminopropoxy, 2-(methylamino)ethoxy,2-(dimethylamino)ethoxy, 3-(dimethylamino)propoxy, cyclopentyloxy,cyclohexyl, cyclohexylamino, 2-hydroxycyclohexylamino, trifluoromethyl,trifluoromethoxy, methylamino, ethylamino, amino (--NH)₂, aminomethyl,aminoethyl, dimethylamino, diethylamino, ethyl(methyl)amino,propyl(methyl)amino, 2-hydroxyethylamino, 3-hydroxypropylamino,4-hydroxybutylamino, 2-aminoethylamino, 3-aminopropylamino,4-aminobutylamino, 2-(methylamino)ethylamino, 2-(ethylamino)ethylamino,2-(i-propylamino)ethylamino, 3-(i-propylamino)propylamino,2-(dimethylamino)ethylamino, 3-(dimethylamino)propylamino,2-(diethylamino)ethylamino, 3-(diethylamino)propylamino,2-(methylamino)ethyl(methyl)amino, 3-(methylamino)propyl(methyl)amino,2-(dimethyl-amino)ethyl(methyl)amino,2-(dimethylamino)ethyl(ethyl)amino, nitro, cyano, hydroxyl (--OH),formyl [HC(O)--], carboxyl (--CO₂ H), --CH₂ CO₂ H, --OCH₂ CO₂ H, --CO₂CH₃, --CO₂ CH₂ CH₃, --CH₂ CO₂ CH₃, --CH₂ CO₂ CH₂ CH₃, --CH₂ CO₂ CH₂phenyl, t-butoxycarbonylmethoxy, acetyl, phenacetyl, thio (--SH),thiomethyl, thioethyl, --SC(NH)NH₂, sulphonyl (--SO₂ H),methylsulphonyl, methylaminosulphonyl, ethylaminosulphonyl,dimethylaminosulphonyl, diethylaminosulphonyl, carboxamido (--CONH₂),methylaminocarbonyl, ethylaminocarbonyl, dimethylaminocarbonyl,diethylaminocarbonyl, methylaminocarbonylmethyl, --NHC(S)NH₂,sulphonylamino (--NHSO₂ H), methylsulphonylamino ethylsulphonylamino,dimethylsulphonylamino, diethylsulphonylamino, sulphonylamino (--NHSO₂NH₂), methylaminosulphonylamino, ethylaminosulphonylamino,dimethylaminosulphonylamino, diethylaminosulphonylamino,methylaminocarbonylamino, ethylaminocarbonylamino,dimethylaminocarbonylamino diethylaminocarbonylamino, acetylamino,aminomethylcarbonylamino, acetylaminomethyl, methoxycarbonylamino,ethoxycarbonylamino, t-butoxycarbonylamino, pyrrolidinyl, piperidinyl,piperazinyl, 4-methylpiperazinyl, homopipeprazinyl, morpholinyl,pyrrolidinylC₁₋₆ alkyl, piperidinylC₁₋₆ alkyl, piperazinylC₁₋₆ alkyl,morpholinylC₁₋₆ alkyl, 2-pyrrolidinylethylamino,2-(1-methylpyrrolidinyl)ethylamino, 1-ethylpyrrolidinylmethylamino,piperidinylamino, 1-benzylpiperidinylamino, 4-(methoxy)phenylamino,4-(3-hydroxypropyl)phenylamino, benzylamino, benzyloxy,pyridiylmethylamino group.

It will be appreciated that where two or more R¹² substituents arepresent, these need not necessarily be the same atoms and/or groups.

In general, when R⁸ is a heteroaliphatic, heterocycloaliphatic orheteroaromatic group it is attached to the remainder of the molecule offormula (1) through any available heteroatom or group or, preferably,carbon atom.

The groups R², R³, R⁷ and additionally R¹⁰ and/or R^(10a) [wherepresent] in compounds of formula (1) may each individually be anoptionally substituted aliphatic, cycloaliphatic, heteroaliphatic,heterocycloaliphatic, aromatic or heteroaromatic group. In each case,the aliphatic, cycloalphatic, heteroaliphatic, heterocycloaliphatic,aromatic or heteroaromatic group may be as particularly described abovefor R⁸ when it represents one of these groups.

Halogen atoms represented by the groups R², R³ and/or R⁶ in compounds offormula (1) include for example fluorine, chlorine, bromine or iodineatoms.

Substituted amino groups represented by the groups R¹, R², R³ and/or R⁶in compounds of formula (1) include groups such as --NHR¹⁵ [where R¹⁵ isan optionally substituted straight or branched C₁₋₆ alkyl, C₂₋₆ alkenylor C₂₋₆ alkynyl group], --NR¹⁵ R¹⁶ [where R¹⁵ and R¹⁶ are the same ordifferent and R¹⁶ is an optionally substituted alkyl, alkenyl or alkynylgroup as just described for R¹⁵ ], --N(R¹⁷)COR¹⁵, [where R¹⁷ is ahydrogen atom or a group R¹⁵ as just described], --N(R¹⁷)SO₂ R¹⁸ (whereR¹⁸ is as described for R¹⁷ ] --N[SO₂ R¹⁸ ]₂, --N(R¹⁷)SO₂ NR¹⁷ R¹⁸,--N(R¹⁷)CONR¹⁷ R¹⁸, or --N(R¹⁷)CSNR¹⁷ R¹⁸. Particular examples of R¹⁵,R¹⁶, R¹⁷ R¹⁸ alkyl, alkenyl or alkynyl groups include optionallysubstituted methyl, ethyl, n-propyl, i-propyl, allyl or ethynyl groups.Optional substituents include those described above in relation to thegroup R⁸ when R⁸ is an optionally substituted aliphatic group.

Particular examples of substituted amino groups represented by R², R³and/or R⁶ include --NHCH₃, --N(CH₃)₂, --NHCH₂ CH₃, --N(CH₂ CH₃)₂,--NHCOCH₃, --NHSO₂ H, --NHSO₂ CH₃, --NHSO₂ NH₂, --NHSO₂ NHCH₃, --NHSO₂N(CH₃)₂, --NHCONH₂, --NHCONHCH₃ or --NHCONHCH₂ CH₃ groups.

Optionally substituted straight or branched alkyl, alkenyl or alkynylgroups represented by R⁵ and/or R^(6a) [when present] include optionallysubstituted C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl as described abovefor R⁸ aliphatic groups.

Straight or branched alkyl groups represented by the group R⁴ incompounds of the invention include straight or branched C₁₋₆ alkylgroups such as methyl or ethyl groups.

The presence of certain substituents in the compounds of formula (1) mayenable salts of the compounds to be formed. Suitable salts includepharmaceutically acceptable salts, for example acid addition saltsderived from inorganic or organic acids, and salts derived frominorganic and organic bases.

Acid addition salts include hydrochlorides, hydrobromides, hydroiodides,alkylsulphonates, e.g. methanesulphonates, ethanesulphonates, orisethionates, arylsulphonates, e.g. p-toluenesulphonates, besylates ornapsylates, phosphates, sulphates, hydrogen sulphates, acetates,trifluoroacetates, propionates, citrates, maleates, fumarates,malonates, succinates, lactates, oxalates, tartrates and benzoates.

Salts derived from inorganic or organic bases include alkali metal saltssuch as sodium or potassium salts, alkaline earth metal salts such asmagnesium or calcium salts, and organic amine salts such as morpholine,piperidine, dimethylamine or diethylamine salts.

Particularly useful salts of compounds according to the inventioninclude pharmaceutically acceptable salts, especially acid additionpharmaceutically acceptable salts.

It will be appreciated that depending on the nature of the substituentsR¹ -R³ and R⁵ -R⁷ the compounds of formula (1) may exist as geometricalisomers and/or may have one or more chiral centres so that enantiomersor diasteromers may exist. It is to be understood that the inventionextends to all such isomers of the compounds of formula (1), and tomixtures thereof, including racemates.

In one class of compounds of formula (1) the groups R¹, R², R³, R⁴, R⁵,R⁷ and X are as defined for formula (1), and R⁶ is a hydrogen or halogenatom or a group --X¹ --R^(6a).

In a further preferred class of compounds of formula (1) R⁴ isespecially a hydrogen atom.

The groups R⁵ and R⁶ in compounds of formula (1) are each preferably ahydrogen atom.

R⁷ in compounds of formula (1) is preferably an optionally substitutedaromatic or heteroaromatic group.

A further class of compounds according to the invention has the formula1(a): ##STR3## wherein each of R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ is asdefined for formula (1); and the salts, solvates, hydrates and N-oxidesthereof.

In these compounds, R⁴ and R⁵ is each preferably a hydrogen atom. R⁶ ispreferably a group --X¹ R^(6a) where X¹ is as defined for formula (1)and R^(6a) is an optionally substituted straight or branched chain alkylgroup, or R⁶ is especially a hydrogen atom. R⁷ in compounds of formula(1a) is preferably an optionally substituted aromatic or heteroaromaticgroup.

The aromatic or heteroaromatic R⁷ group in compounds of formulae (1) or1(a) in general may be as defined previously for compounds of formula(1). In one preference, however, R⁷ is an optionally substituted phenyl,1- or 2-naphthyl or heteroaromatic group containing one or two oxygen,sulphur and/or nitrogen atoms. Thus in particular R⁷ may be anoptionally substituted phenyl, 1- or 2-naphthyl, pyrrolyl, furyl,thienyl, indolyl, pyrazolyl, thiazolyl, [2,3-dihydro]benzofuryl,benzothiazolyl, 2-pyridyl, 3-pyridyl or 4-pyridyl group. Particularlyuseful groups include optionally substituted phenyl, particularly3-substituted phenyl groups, 2-pyridyl, 3-pyridyl or 4-pyridyl groups.The aromatic or heteroaromatic group may in particular be attached tothe remainder of the compound of formula (1) through any available ringcarbon atom.

In general, the optional substituents which may be present on aromaticor heteroaromatic R⁷ groups in compounds of formulae (1) or (1a) includeone, two, or three R¹² substituents as generally and particularlydescribed above and hereinafter in the Examples. Particularly useful R¹²substituents include --NHR¹⁴, -AlkNH₂, -AlkNHR¹⁴, --OR¹⁴, -AlkCO₂ H or-AlkCO₂ Alk¹ groups where R¹⁴, Alk and Alk¹ are as generally andparticularly defined above. Useful members of these substituents includethose wherein R¹⁴ is an -Alk, -AlkNH₂ or -Alk-heterocycloalkyl group. Inthese, and the other preferred substituents just mentioned, Alk and Alk¹when present is each preferably a C₁₋₆ alkyl group.

In the compounds of formula (1) and (1a) R¹ is preferably an --R⁸ or inparticular an --OR⁸ group. The group R¹ is preferably attached at the 3-or 4-position of the phenyl ring. When R¹ is at the 3-position any R²and/or R³ substituent is preferably at the 4- and/or 5-positions. WhenR¹ is at the 4-position any R² and/or R³ substituent is preferablyattached at the 3- and/or 5-positions.

Particularly useful --R⁸ groups include heterocycloaliphatic groups ofthe type generally described above, especially optionally substitutedC₃₋₇ cycloalkyl groups containing one or two heteroatoms such aspyrrolidinyl or morpholinyl groups. Particularly useful --OR⁸ groupsinclude optionally substituted alkoxy groups such as optionallysubstituted ethoxy groups. Particularly useful substituents includeamino or substituted amino groups or, especially, --NHet¹ groups where--NHet¹ is as defined above.

In these last compounds, and in general, the groups R² and R³ is eachpreferably a methyl or methoxy group or a hydrogen atom.

Particularly useful compounds according to the invention are:

4-(3-methoxyphenylsulphanyl)-N-{[3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy]phenyl}-2-pyrimidineamine;

4-(3-Carboxyphenylsuphanyl)-N-{[3,5-dimethyl-4-(2-pyrrolidin-1-yl)ethoxy]phenyl}-2-pyrimidineamine;

N-[4,5-Dimethoxy-3-(2-pyrrolidin-1-ylethoxy)]-4-(3-methoxyphenylsulphanyl)-2-pyrimidineamine;

4-(3-Methoxyphenylsulphanyl)-N-{4-methoxy-[3-(2-pyrrolidin-1-yl)ethoxy]phenyl}2-pyrimidineamine;

N-{3,5-Dimethoxy-4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}-4-(3-methoxyphenylsulphanyl)-2-pyrimidineamine;

N-{[4,5-Dimethoxy-3-(2-pyrrolin-1-yl)ethoxy]phenyl}-4-(4-fluorophenylsulphanyl)pyrimidine-2-amine;

4-(3-Bromophenylsulphanyl)-N-[4,5-dimethoxy-3-(2-pyrrolidin-1-ylethoxy)phenyl]-2-pyrimidineamine;

N-{3,5-Dichloro-4-[(2-pyrrolidin-1-yl)ethoxy]phenyl}-4-(3,5-dimethylphenylsulphanyl)-2-pyrimidineamine;

and the salts, solvates and hydrates thereof.

Compounds according to the invention are potent and selective inhibitorsof protein kinases, especially those of the src family, as demonstratedby their inhibition of enzymes such as p56^(lck) and p59^(fyn). Theability of the compounds to act in this way may be simply determined byemploying tests such as those described in the Examples hereinafter.

The compounds according to the invention are thus of particular use inthe prophylaxis and treatment of diseases in which inappropriate proteintyrosine kinase action plays a role, for example in autoimmune diseasessuch as rheumatoid arthritis, multiple sclerosis, and systemic lupuserythematosus, in transplant rejection, in graft v host disease, inhyperproliferative disorders such as tumours, psoriasis, in pannusformation in rheumatoid arthritis, restenosis following angioplasty andatherosclerosis, in osteoporosis and in diseases in which cells receiveproinflammatory signals such as asthma, inflammatory bowel disease andpancreatitis.

For the prophylaxis or treatment of disease the compounds according tothe invention may be administered as pharmaceutical compositions, andaccording to a further aspect of the invention we provide apharmaceutical composition which comprises a compound of formula (1)together with one or more pharmaceutically acceptable carriers,excipients or diluents.

Pharmaceutical compositions according to the invention may take a formsuitable for oral, buccal, parenteral, nasal, topical or rectaladministration, or a form suitable for administration by inhalation orinsufflation.

For oral administration, the pharmaceutical compositions may take theform of, for example, tablets, lozenges or capsules prepared byconventional means with pharmaceutically acceptable excipients such asbinding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidoneor hydroxypropyl methylcellulose); fillers (e.g. lactose,microcrystalline cellulose or calcium hydrogen phosphate); lubricants(e.g. magnesium stearate, talc or silica); disintegrants (e.g. potatostarch or sodium glycollate); or wetting agents (e.g. sodium laurylsulphate). The tablets may be coated by methods well known in the art.Liquid preparations for oral administration may take the form of, forexample, solutions, syrups or suspensions, or they may be presented as adry product for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents,emulsifying agents, non-aqueous vehicles and preservatives. Thepreparations may also contain buffer salts, flavouring, colouring andsweetening agents as appropriate.

Preparations for oral administration may be suitably formulated to givecontrolled release of the active compound.

For buccal administration the compositions may take the form of tabletsor lozenges formulated in conventional manner.

The compounds for formula (1) may be formulated for parenteraladministration by injection e.g. by bolus injection or infusion.Formulations for injection may be presented in unit dosage form, e.g. inglass ampoule or multi dose containers, e.g. glass vials. Thecompositions for injection may take such forms as suspensions, solutionsor emulsions in oily or aqueous vehicles, and may contain formulatoryagents such as suspending, stabilising, preserving and/or dispersingagents. Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g. sterile pyrogen-free water,before use.

In addition to the formulations described above, the compounds offormula (1) may also be formulated as a depot preparation. Such longacting formulations may be administered by implantation or byintramuscular injection.

For nasal administration or administration by inhalation, the compoundsfor use according to the present invention are conveniently delivered inthe form of an aerosol spray presentation for pressurised packs or anebuliser, with the use of suitable propellant, e.g.dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas ormixture of gases.

The compositions may, if desired, be presented in a pack or dispenserdevice which may contain one or more unit dosage forms containing theactive ingredient. The pack or dispensing device may be accompanied byinstructions for administration.

The quantity of a compound of the invention required for the prophylaxisor treatment of a particular condition will vary depending on thecompound chosen, and the condition of the patient to be treated. Ingeneral, however, daily dosages may range from around 100 ng/kg to 100mg/kg e.g. around 0.01 mg/kg to 40 mg/kg body weight for oral or buccaladministration, from around 10 ng/kg to 50 mg/kg body weight forparenteral administration and around 0.05 mg to around 1000 mg e.g.around 0.5 mg to around 1000 mg for nasal administration oradministration by inhalation or insufflation.

The compounds of the invention may be prepared by a number of processesas generally described below and more specifically in the Exampleshereinafter. In the following process description, the symbols R¹ -R⁷when used in the formulae depicted are to be understood to representthose groups described above in relation to formula (1) unless otherwiseindicated. In the reactions described below, it may be necessary toprotect reactive functional groups, for example hydroxy, amino, thio orcarboxy groups, where these are desired in the final product, to avoidtheir unwanted participation in the reactions. Conventional protectinggroups may be used in accordance with standard practice [see, forexample, Green, T. W. in "Protective Groups in Organic Synthesis", JohnWiley and Sons, 1991]. In some instances, deprotection may be the finalstep in the synthesis of a compound of formula (1) and the processesaccording to the invention described hereinafter are to be understood toextend to such removal of protecting groups.

Thus according to one aspect of the invention, a compound of formula (1)wherein R⁴ is a hydrogen atom may be prepared by displacement of aleaving atom or group in a pyrimidine of formula (2): ##STR4## [where Lis a leaving atom or group] with an aniline of formula (3): ##STR5##

Particular leaving atoms or groups represented by L include for examplehalogen atoms, e.g. bromine, iodine or chlorine atoms, and sulphonyloxygroups, e.g. alkylsulphonyloxy groups, such astrifluoromethylsulphonyloxy, and arylsulphonyloxy groups, such asp-toluenesulphonyloxy.

The reaction may be performed at an elevated temperature, for examplethe reflux temperature, where necessary in the presence of a solvent,for example a ketone such as acetone, an alcohol such as ethanol or2-ethoxyethanol or an aromatic hydrocarbon such as toluene, optionallyin the presence of a base, for example an organic amine such astriethylamide or pyridine, or an acid, for example an inorganic acidsuch as hydrochloric acid.

Intermediate pyrimidines of formula (2) are either known readilyavailable compounds or may be prepared by displacement of a leavinggroup from a pyrimidine of formula (4): ##STR6## [where L¹ is a leavingatom or group as described above for the group L] using a thiol R⁷ SH.The reaction may be performed in the presence of a base such as sodiumhydride in a solvent such as an amide, e.g. dimethylformamide at a lowtemperature of around 0° C.

The pyrimidines of formula (4) and the nucleophilic reagents R⁷ SH areeither known compounds or may be prepared using methods analogous tothose used for the preparation of the known compounds.

The anilines of formula (3) are either known compounds or may beobtained by conventional procedures, for example by hydrogenation of thecorresponding nitro derivatives using for example hydrogen in thepresence of a metal catalyst in a suitable solvent, for example as moreparticularly described in the interconversion reactions discussed below,or by use of the corresponding nitro derivative and a reducing agentsuch as sodium hydrosulphite in a solvent such as ethanol at an elevatedtemperature such as the reflux temperature. The nitrobenzenes for thisparticular reaction are either known compounds or may be prepared usingsimilar methods to those used for the preparation of the knowncompounds, for example by treatment of the corresponding benzene withnitric acid in the presence of an acid such as acetic acid at aroundambient to the reflux temperature.

Compounds of formula (1) may also be prepared by interconversion ofother compounds of formula (1) and it is to be understood that theinvention extends to such interconversion processes. Thus, for example,standard substitution approaches employing for example alkylation,arylation, acylation, thioacylation, sulphonylation, formylation orcoupling reactions may be used to add new substitutents to and/or extendexisting substituents in compounds of formula (1). Alternativelyexisting substituents in compounds of formula (1) may be modified by forexample oxidation, reduction or cleavage reactions to yield othercompounds of formula (1).

The following describes in general terms a number of approaches whichcan be employed to modify existing R¹, R², R³, R⁴, R⁵, R⁶ and/or R⁷groups in compounds of formula (1). It will be appreciated that each ofthese reactions may only be possible where an appropriate functionalgroup exists in a compound of formula (1). Equally, any of the followingreactions may be used to generate appropriately substitutedintermediates of formulae (2), (3) and (4) for use in the preparation ofcompounds of formula (1).

Thus, for example alkylation or arylation of a compound of formula (1)may be achieved by reaction of the compound with a reagent R⁸ L (whereR⁸ is as defined above except for a hydrogen atom) or (R¹³)_(m) AlkLwhere L is as previously defined.

The alkylation or arylation reaction may be carried out in the presenceof a base, e.g. an inorganic base such as a carbonate, e.g. caesium orpotassium carbonate, an alkoxide, e.g. potassium t-butoxide, or ahydride, e.g. sodium hydride, in a dipolar aprotic solvent such as anamide, e.g. a substituted amide such as dimethylformamide or an ether,e.g. a cyclic ether such as tetrahydrofuran, at around 0° C. to around400° C.

In a variation of this process the leaving group L may be alternativelypart of the compound of formula (1) and the reaction performed with anappropriate nucleophilic reagent such as an amine in a solvent such asan alcohol, e.g. ethanol, or an amide such as dimethylformamide at anelevated temperature, e.g. the reflux temperature.

In another general example of an interconversion process, a compound offormula (1) may be acylated or thioacylated. The reaction may beperformed for example with an acyl halide or anhydride in the presenceof a base, such as a tertiary amine e.g. triethylamine in a solvent suchas a halogenated hydrocarbon, e.g. dichloromethane or carbontetrachloride, or an alcohol, e.g. methanol at for example ambienttemperature, or by reaction with a thioester in an inert solvent such astetrahydrofuran at a low temperature such as around 0° C. The reactionis particularly suitable for use with compounds of formula (1)containing primary or secondary amino groups.

In a further general example of an interconversion process, a compoundof formula (1) may be formylated, for example by reaction of thecompound with a mixed anhydride HCOOCOCH₃ or with a mixture of formicacid and acetic anhydride.

Compounds of formula (1) may be prepared in another generalinterconversion reaction by sulphonylation, for example by reaction ofthe compound with a reagent (R¹³)_(m) AlkS(O)₂ L, or R⁸ S(O)₂ L in thepresence of a base, for example an inorganic base such as sodium hydridein a solvent such as an amide, e.g. a substituted amide such asdimethylformamide at for example ambient temperature. The reaction mayin particular be performed with compounds of formula (1) possessingprimary or secondary amino group.

In further examples of interconversion reactions according to theinvention compounds of formula (1) may be prepared from other compoundsof formula (1) by modification of existing functional groups in thelatter.

Thus in one example, ester groups --CO₂ Alk¹ in compounds of formula (1)may be converted to the corresponding acid [--CO₂ H] by acid- orbase-catalysed hydrolysis or by catalytic hydrogenation depending on thenature of the group Alk¹. Acid- or base-catalysed hydrolysis may beachieved for example by treatment with an organic or inorganic acid,e.g. trifluoroacetic acid in an aqueous solvent or a mineral acid suchas hydrochloric acid in a solvent such as dioxan or an alkali metalhydroxide, e.g. lithium hydroxide in an aqueous alcohol, e.g. aqueousmethanol. Catalytic hydrogenation may be carried out using for examplehydrogen in the presence of a metal catalyst, for example palladium on asupport such as carbon in a solvent such as an ether, e.g.tetrahydrofuran or an alcohol, e.g. methanol. Similarly, base-catalysedhydrolysis with for example an alkali metal hydroxide such as sodiumhydroxide in a solvent such as an alcohol e.g. ethanol may be used toconvert a >NSO₂ Alk(R¹³)_(m) or >NSO₂ R⁸ group to a >N--H group.

In a second example, --OAlk² [where Alk² represents an alkyl group suchas a methyl group] groups in compounds of formula (1) may be cleaved tothe corresponding alcohol [--OH] by reaction with boron tribromide in asolvent such as a halogenated hydrocarbon, e.g. dichloromethane at a lowtemperature, e.g. around -78° C.

Alcohol [--OH] groups may also be obtained by hydrogenation of thecorresponding --OCH₂ R⁸ group in which R⁸ is an aromatic group using forexample hydrogen in the presence of a metal catalyst, for examplepalladium on a support such as carbon in a solvent such as ethanol inthe presence of ammonium formate. In another example, --OH groups may begenerated from the corresponding ester [--CO₂ Alk] by reduction usingfor example a complex metal hydride such as lithium aluminium hydride.

In a further example, alcohol --OH groups in compounds of formula (1)may be converted to a corresponding --OAlk (R¹³)_(m) or --OR⁸ groupwhere R⁸ is as described for formula (1) other than a hydrogen atom bycoupling with a reagent (R¹³)_(m) AlkOH or R⁸ OH in a solvent such astetrahydrofuran in the presence of a phosphine, e.g. triphenylphosphineand an activator such as diethyl-, diisopropyl-, ordimethylazodicarboxylate.

In another example of an interconversion reaction, amines of formula (1)may be alkylated using a reductive alkylation process employing analdehyde and a borohydride, for example sodium triacetoxyborohydride, ina solvent such as dichloromethane, in the presence of an acid such asacetic acid at around ambient temperature.

In a further example, amide groups in compounds of formula (1) may beobtained by coupling an acid [--CO₂ H] or an active derivative thereof,e.g. an acid anhydride, ester, imide or halide, with an amine in whicheither the acid or amine forms part of the starting material of formula(1). The coupling reaction may be performed using standard conditionsfor reactions of this type. Thus for example the reaction may be carriedout in a solvent, for example an inert organic solvent such as an amide,e.g. a substituted amide such as dimethylformamide, at a lowtemperature, e.g. -30° C. to ambient temperature, optionally in thepresence of a base, e.g. an organic base such as a cyclic amine, e.g.N-methylmorpholine, and where necessary in the presence of a condensingagent, for example a diimide such as1-(3-dimethylaminopropyl)-3-ethylcarbodiimide advantageously in thepresence of a catalyst such as a N-hydroxy compound, e.g. aN-hydroxytriazole such as hydroxyazabenzotriazole.

Urea groups in compounds of formula (1) may be prepared by reaction of acorresponding amine [--NH₂ ] with an isocyanate, e.g. ethyl isocyanate,in a solvent, e.g. dichloromethane, at ambient temperature.

Aminosulphonylamino [--NHSO₂ NH₂ ] groups in compounds of formula (1)may be obtained, in another example, by reaction of a correspondingamine [--NH₂ ] with sulphamide in the presence of an organic base suchas pyridine at an elevated temperature, e.g. the reflux temperature.

In a further example, amine [--NH₂ ] groups in compounds of formula (1)may be obtained by hydrolysis from a corresponding imide by reactionwith hydrazine in a solvent such as an alcohol, e.g. ethanol at ambienttemperature.

In another example, a nitro [--NO₂ ] group may be reduced to an amine[--NH₂ ], for example by catalytic hydrogenation as just described, orby chemical reduction using for example a metal, e.g. tin or iron,optionally in the presence of an acid such as hydrochloric acid and asolvent such as an alcohol, e.g. methanol or ethanol.

In a further example of an interconversion process, a tetrazolesubstituent may be obtained from the corresponding nitrile by treatmentof the latter with an azide, e.g. sodium azide, in a solvent such as asubstituted amine, e.g. dimethylformamide at an elevated temperature.

N-oxides of compounds of formula (1) may be prepared for example byoxidation of the corresponding nitrogen base using an oxidising agentsuch as hydrogen peroxide in the presence of an acid such as aceticacid, at an elevated temperature, for example around 70° C. to 80° C.,or alternatively by reaction with a peracid such as peracetic acid or3-chloroperoxybenzoic acid in a solvent, e.g. dichloromethane, atambient temperature.

Where salts of compounds of formula (1) are desired, these may beprepared by conventional means, for example by reaction of a compound offormula (1) with an appropriate acid or base in a suitable solvent ormixture of solvents, e.g. an organic solvent such as an ether, e.g.diethylether, or an alcohol, e.g. ethanol.

The following Examples illustrate the invention. In the Examples all ¹Hnmr were run at 300 MHz unless specified otherwise. All temperaturesare in °C. The following abbreviations are used:DMSO--dimethylsulphoxide; DMF--dimethylformamide. In many of thefollowing Examples 2-chloro-4-(3-methoxyphenylsulphanyl)pyrimidine isused as a starting material.

The preparation of this compound is described in Example 1. Where it isused in other Examples it is referred to as Intermediate A.

EXAMPLE 14-(3-Methoxyphenylsulphanyl)-N-[3,5-dimethyl-4-(2-pyrrolidin-1-yl)ethoxy]phenyl}-2-pyrimidineaminedihydrochloride

A mixture of 2-chloro-4-(3-methoxyphenylsulphanyl)pyrimidine (140 mg,0.55 mmol) and 3,5-dimethyl-4-(2-(1-pyrrolidino)ethoxy)aniline (130 mg,0.55 mmol) was heated at reflux under a nitrogen atmosphere inethoxyethanol (4 ml) containing 1M hydrochloric acid in diethyl ether(0.55 ml), for 2 h. After this time the solvent was removed underreduced pressure, the residue partitioned between CH₂ Cl₂ and saturatedaqueous NaHCO₃ solution, and the organic phase was dried (MgSO₄) andconcentrated. The residue was subjected to column chromatography(silica, 5% methanol-CH₂ Cl₂) and the product dissolved in ethyl acetate(5 ml) and treated with 1M hydrochloric acid in diethyl ether. Theresulting precipitate was collected and dried to give the title compound(100 mg) as a yellow solid m.p. 94-96°. δ_(H) (d⁶ DMSO) 11.21 (1H, brs), 9.73 (1H, br s), 8.17 (1H, d, J 5.6 Hz), 7.46-7.41 (1H, m), 7.23(2H, s), 7.21-7.18 (2H, m), 7.13-7.10 (1H, m), 6.34 (1H, d, J 5.2 Hz),4.34 (1H, br s), 4.10-4.04 (2H, m), 3.75 (3H, s), 3.65-3.53 (4H, m),3.20-3.11 (2H, m), 2.16 (6H, s) and 2.02-1.94 (4H, m).

The 2-chloro-4-(3-methoxyphenylsulphanyl)pyrimidine used as startingmaterial was prepared by adding a solution of 3-methoxybenzenethiol(0.84 ml, 6.71 mmol) in dry DMF (30 ml) to a suspension of sodiumhydride [60% dispersion in oil] (295 mg, 7.40 mmol) in DMF (30 ml) at0°, and stirring for 10 min before addition of 2,4-dichloropyrimidine(1.0 g, 6.71 mmol). After continued stirring at 0° for 2 h, the solventwas removed under reduced pressure and the residue partitioned betweenethyl acetate (100 ml) and 1M aqueous NaOH (75 ml). The organic layerwas dried, concentrated under reduced pressure and the residue subjectedto column chromatography. The resulting oil was taken up in diethylether-hexane to give the desired product (1.08 g) as a white solid, m.p.65-66°. δ_(H) (CDCl₃) 8.18 (1H, d, J 5.4 Hz), 7.41 (1H, t, J 8.09 Hz),7.20-7.05 (3H, m), 6.65 (1H, d, J 5.4 Hz) and 3.85 (3H, s).

The compounds of Examples 2 and 3 were prepared in a similar manner:

EXAMPLE 2N-(4-(2-Dimethylaminoethoxy)phenyl)-4-(4-methoxyphenylsulphanyl)-2-pyrimidineamine

From 4-(2-dimethylaminoethoxy)aniline (180 mg, 1.0 mmol),2-chloro-4-(4-methoxyphenylsulphanyl)pyrimidine (253 mg, 1.0 mmol) and1M hydrochloric acid in diethyl ether (1.0 ml, 1.0 mmol) to give thetitle compound (160 mg) as a white solid m.p. 112-113°. δH (CDCl₃) 7.99(1H, d, J 5.4 Hz), 7.51 (2H, d, J 8.7 Hz), 7.27 (2H, d, J 9.0 Hz),6.99-6.96 (3H, m), 6.78 (2H, d, J 9.0 JHz), 6.23 (1H, d, J 5.4 Hz), 4.04(2H, t, J 5.7 Hz), 3.87 (3H, s), 2.73 (2H, t, J 5.7 Hz) and 2.34 (6H,s).

The 2-chloro-4-(4-methoxyphenylsulphanyl)pyrimidine was prepared in asimilar manner to the analogous starting material of Example 1, from4-methoxybenzenethiol (1.90 g, 13.4 mmol), 2,4-dichloropyrimidine (2.0g, 13.4 mmol) and sodium hydride [60% dispersion in oil] (590 mg, 14.8mmol) as an off-white solid m.p. 69-70°.

EXAMPLE 34-(3-Methoxyphenylsulphanyl)-N-[3-(4-methylpiperazinyl)phenyl]-2-pyrimidneamine

From Intermediate A (436 mg, 1.72 mmol),3-(4-methylpiperazin-1-yl)aniline (330 mg, 1.72 mmol) and 1M hydrogenchloride in diethyl ether (1.72 ml) to give the title compound (70 mg)as a yellow solid m.p. 105-106°. δH (CDCl₃) 8.04 (1H, d, J 5.4 Hz),7.04-6.95 (2H, m), 6.59 (1H, dd, J 8.0, 1.8 Hz), 6.26 (1H, d, J 5.4 Hz),3.81 (3H, s), 3.23-3.19 (4H, m), 2.58-2.54 (4H, m) and 2.34 (3H, s).

EXAMPLE 4N-(4-Hydroxyphenyl)-4-(4-methylphenylsulphanyl)-2-pyrimidineamine

A mixture of 2-chloro-4-(4-methylphenylsulphanyl)pyrimidine (100 mg,0.42 mmol) and 4-aminophenol (55 mg, 0.5 mmol) was heated at reflux inethoxyethanol (2 ml) for 1.5 h. The reaction was concentrated underreduced pressure and subjected to column chromatography [silica, 20%ethyl acetate--CH₂ Cl₂ ] to give the title compound (60 mg) as a buffsolid m.p. 179-180°. δH (CDCl₃) 8.01 (1H, d, J 5.4 Hz), 7.50-7.45 (2H,m), 7.31-7.27 (4H, m), 6.93 (1H, br s), 6.71-6.66 (2H, m), 6.25 (1H, d,J 5.4 Hz), 4.70 (1H, br s) and 2.44 (3H, s).

The 2-chloro-4-(4-methylphenylsulphanyl)pyrimidine was prepared in asimilar manner to the analogous starting material of Example 1, fromp-thiocresol (838 mg, 6.71 mmol), 2,4-dichloropyrimidine (1.0 g, 6.71mmol) and sodium hydride [60% dispersion in oil] (295 mg, 7.4 mmol),m.p. 80-81°. δH (CDCl₃) 8.15 (1H, d, J 5.4 Hz), 7.46 (2H, d, J 8.0 Hz),7.30 (2H, d, J 8.0 Hz), 6.59 (1H, d, J 5.4 Hz) and 2.43 (3H, s).

The compounds of Examples 5-17 were prepared in a similar manner to thecompound of Example 4:

EXAMPLE 5N-(4-Benzyloxyphenyl)-4-(4-methoxyphenylsulphanyl)-2-pyrimidine

From 2-chloro-4-(4-methoxyphenylsulphanyl)pyrimidine (7.51 g, 6.0mmol--see Example 2) and 4-benzyloxyaniline (2.83 g, 12.9 mmol) to givethe title compound (1.60 g) as a white solid m.p. 146-147°. δH (CDCl₃)8.00 (1H, d, J 5.4 Hz), 7.53 (2H, d, J 8.8 Hz), 7.45-7.27 (7H, m),7.02-6.96 (3H, m), 6.85 (2H, d, J 9.0 Hz), 6.24 (1H, d, J 5.4 Hz), 5.04(2H, s) and 3.88 (3H, s).

EXAMPLE 64-(3-Methoxyphenylsulphanyl)-N-(4-morpholinophenyl)-2-pyrimidineamine

From Intermediate A (300 mg, 1.19 mmol) and 4-morpholinoaniline (211 mg,1.19 mmol) to give the title compound as an off-white solid m.p.159-161°. δH (CDCl₃) 8.01 (1H, dd, J 5.3, 2.7 Hz), 7.40-7.37 (3H, m),7.33 (1H, dd, J 6.5, 2.1 Hz), 7.30 (1H, br s), 7.05-7.01 (1H, m), 6.96(1H, s), 6.80 (2H, d, J 8.9 Hz), 6.27 (1H, dd, J 5.3, 2.7 Hz), 3.88-3.83(4H, m), 3.80 (3H, s), 3.11-3.08 (4H, m).

EXAMPLE 7N-(3-Hydroxyphenyl)-4-(3-methoxyphenylsulphanyl)-2-pyrimidineaminehydrochloride

From Intermediate A (1.0 g, 3.96 mmol) and 3-aminophenol (437 mg, 4.0mmol) to give the title compound (930 mg) as a white solid m.p.144-145°. δH (CDCl₃) 8.06 (1H, d, J 5.4 Hz), 7.39 (1H, t, J 7.9 Hz),7.26-7.03 (5H, m), 6.71 (1H, dd, J 7.9, 1.6 Hz), 6.46 (1H, dd, J 7.9,2.4 Hz), 6.42 (1H, d, J 5.4 Hz), 5.57 (1H, br s) and 3.82 (3H, s).

EXAMPLE 8N-(4-Carboxyphenyl)-4-(3-methoxyphenylsulphanyl)pyrimidine-2-aminehydrochloride

From Intermediate A (500 mg, 1.98 mmol) and 4-aminobenzoic acid (274 mg,2.0 mmol) to give the title compound (350 mg) as a yellow solid m.p.242-243°. δH (d⁶ DMSO) 10.21 (1H, br s), 8.25 (1H, d, J 5.5 Hz), 7.69(2H, d, J 8.8 Hz), 7.56 (2H, d, J 8.8 Hz), 7.48 (1H, t, J 8.1 Hz),7.23-7.16 (3H, m), 6.62 (1H, d, J 5.5 Hz) and 3.78 (3H, s).

EXAMPLE 9N-(3-Hydroxy-4-methoxy)phenyl-4-(3-methoxyphenylsulphanyl)-2-pyrimidineamine

From Intermediate A (4.55 g, 18 mmol) and 5-amino-2-methoxyphenol (2.51g, 18 mmol) to give the title compound as a yellow solid m.p. 182-183°.δH (CDCl₃) 10.40 (1H, br s), 7.77 (1H, d, J 6.6 Hz), 7.45-7.39 (1H, m),7.15 (1H, d, J 7.8 Hz), 7.10-7.07 (2H, m), 6.99 (1H, d, J 2.5 Hz), 6.78(1H, dd, J 8.7, 2.5 Hz), 6.65 (1H, d, J 8.7 Hz), 6.47 (1H, d, J 6.6 Hz),5.63 (1H, br s), 3.87 (3H, s) and 3.78 (3H, s).

EXAMPLE 10N-[3-(2-Hydroxyethyl)phenyl]-4-(3-methoxyphenylsulphanyl)-2-pyrimidineamine

From Intermediate A (1.07 g, 4.2 mmol) and 3-aminophenethyl alcohol (576mg, 4.2 mmol) to give the title compound (1.1 g) as a yellow solid m.p.122-124°. δH (CDCl₃) 8.05 (1H, d, J 5.4 Hz), 7.40-7.30 (3H, m),7.22-7.13 (4H, m), 7.03 (1H, ddd, J 8.3, 2.6, 1.0Hz), 6.86 (1H, d, J 7.6Hz), 6.32 (1H, d, J 5.4 Hz), 3.86-3.81 (5H, m) and 2.81 (2H, t, J 6.5Hz).

EXAMPLE 11N-[3-Hydroxy-5-(1,1,1-trifluoromethyl)phenyl]-4-(3-methoxyphenylsulphanyl)-2-pyrimidineaminehydrochloride

From Intermediate A (2.0 g, 7.9 mmol) and3-amino-5-(1,1,1-trifluoromethyl)phenyl (1.4 g, 7.9 mmol) to give thetitle compound (2.0 g) as a white solid m.p. 163-164°. δH (d⁶ DMSO) 9.98(1H, br s), 8.22 (1H, d, J 5.4 Hz), 7.56 (1H, s), 7.48-7.43 (2H, m),7.24-7.21 (2H, m), 7.15-7.12 (1H, m), 6.66 (1H, s), 6.24 (1H, d, J 5.4Hz) and 3.79 (3H, s).

EXAMPLE 12N-(3-Hydroxymethyl)phenyl-4-(3-methoxyphenylsulphanyl)-2-pyrimidineaminehydrochloride

From Intermediate A (3.79 g, 15 mmol) and 3-aminobenzyl alcohol (1.85 g,15 mmol) to give the title compound (3.14 g) as a yellow solid m.p.124-125°. δH (d⁶ DMSO) 10.18 (1H, br s), 8.22 (1H, d, J 5.7 Hz), 7.88(1H, br s), 7.49-7.36 (4H, m), 7.22-7.14 (3H, m), 7.07 (1H, t, J 7.7Hz), 6.93 (1H, d J 7.6 Hz), 6.52 (1H, d, J 5.7 Hz), 4.41 (2H, s) and3.77 (3H, s).

EXAMPLE 13N-(3-Aminomethylphenyl)-4-(3-methoxyphenylsulphanyl)-2-pyrimidineamine

From Intermediate A (2.53 g, 10 mmol) and 3-aminobenzylaminehydrochloride (1.59 g, 10 mmol) to give the title compound (1.5 g) as ayellow solid m.p. 120-121°. δH (d⁶ DMSO) 10.11 (1H, br s), 8.54 (3H, brs), 8.23 (1H, d, J 5.6 Hz), 7.52-7.44 (3H, m), 7.22-7.15 (5H, m), 6.50(1H, d, J 5.6 Hz), 3.88-3.86 (2H, br m) and 3.77 (3H, s).

EXAMPLE 14N-(3-Chloro-4-hydroxy-5-methyl)-4-(3-methoxyphenylsulphanyl)pyrimidine

From Intermediate A (0.5 g, 1.98 mmol) and4-amino-2-chloro-6-methylphenol (312 mg, 1.98 mmol) to give the titlecompound (247 m) as a yellow solid m.p. 161°. δH (d⁶ DMSO) 9.87 (1H, brs), 8.13 (1H, d, J 5.3 Hz), 7.48 (1H, s), 7.38 (2H, m), 7.21-7.16 (3H,m), 7.11 (1H, m), 6.31 (1H, d, J 5.3 Hz), 3.72 (3H, s) and 2.13 (3H, s).

EXAMPLE 154-(3-Bromophenylsulphanyl)-N-(3-nitrophenyl)-2-pyrimidineamine

From 4-(3-bromophenylsulphanyl)-2-chloropyrimidine (3.0 g, 9.95 mmol)and 3-nitroaniline (1.38 g, 9.95 mmol) to give the title compound (3.2g) as a yellow solid m.p. 208-209°. δH (d⁶ DMSO) 10.23 (1H, s), 8.51(1H, s), 8.28 (1H, d, J 5.4 Hz), 7.89-7.69 (5H, m), 7.47 (1H, t, J 7.5Hz), 7.39 (1H, t, J 7.4 Hz) and 6.58 (1H, d, J 5.4 Hz).

The chloropyrimidine starting material was prepared in a similar mannerto Intermediate A as a colourless solid m.p. 60-61°. δH (CDCl₃) 8.23(1H, d, J 5.4 Hz), 7.76 (1H, t, J 1.8 Hz), 7.65 (1H, ddd, J 7.9, 1.8,1.1 Hz), 7.56-7.52 (1H, m), 7.37 (1H, t, J 7.8 Hz) and 6.70 (1H, d, J5.4 Hz).

EXAMPLE 16N-[3-(2-Hydroxyethoxy)phenyl]-4-(3-nitrophenylsulphanyl)-2-pyrimidineamine

From 2-chloro(3-nitrophenylsulphanyl)pyrimidine (1.0 g, 3.75 mmolprepared from 2,4-dichloropyrimidine and 3-nitrobenzenethiol accordingto the method of Example 1) and 3-aminophenethyl alcohol (514 mg 3.75mmol) to give the title compound (350 mg) as a yellow powder m.p.160-161. δH (CDCl₃) 8.46 (1H, t, J 1.9 Hz), 8.34-8.30 (1H, m), 8.11 (1H,d, J 5.3 Hz), 7.93-7.89 (1H, m), 7.62 (1H, t, J 8.0 Hz), 7.20-7.12 (3H,m), 7.03 (1H, t, J 7.8 Hz), 6.84 (1H, d, J 7.5 Hz), 6.48 (1H, d, J 5.3Hz), 3.81 (2H, t, J 6.4 Hz) and 2.76 (1H, t, J 5.6 Hz).

EXAMPLE 174-(3-Carboxyphenylsuphanyl)-N-{[3,5-dimethyl-4-(2-pyrrolidin-1-yl)ethoxy]phenyl}-2-pyrimidineaminesodium salt

From 4-(3-tert-butyoxycarbonylphenylsulphanyl)-2-chloropyrimidine (300mg, 0.93 mmol) and 3,5-dimethyl-4-(2-pyrrolidinyl-1-yl)ethoxyaniline(234 mg, 1.0 mmol) to give the title compound (175 mg) as an off whitesolid m.p. 155-156°. δH (d⁶ DMSO) 8.96 (1H, s), 8.14 (1H, d, J 5.2 Hz),8.10-8.04 (2H, m), 7.79 (1H, d, J 7.9 Hz), 7.58 (1H, t, J 7.8 Hz), 7.17(2H, s), 6.37 (1H, d, J 5.2 Hz), 4.74 (4H, br s), 3.82 (2H, t, J 6.1Hz), 2.86 (3H, t, J 6.2 Hz), 2.64-2.62 (4H, br m), 2.13 (6H, s) and1.74-1.72 (4H, br m).

The sodium salt was formed as a result of partitioning the crudereaction residue between saturated aqueous NaHCO₃ and chloroform. Thesalt was extracted into the organic phase.

The chloropyrimidine starting material was prepared by treating asolution of 4-(3-carboxyphenylsulphanyl)-2-chloropyrimidine (500 mg,1.87 mmol) in CH₂ Cl₂ (25 ml) with concentrated H₂ SO₄ (5 drops),cooling to -78° and condensing isobutylene gas (approximately 10 g) intothe reaction vessel.

After condensation was complete, the cold bath was removed and thesolution left at room temperature for 4 h. The reaction was washed with2M NaOH, dried (MgSO₄) and evaporated to give the desired material (300mg) as a colourless gum which was used for the above process withoutpurification.

4-(3-Carboxyphenylsulphanyl)-2-chloropyrimidine was prepared by heatinga solution of 2,4-dichloropyrimidine (2.97 g, 19.9 mmol) and3-mercaptobenzoic acid (3.07 g, 19.9 mmol) in ethanol (50 ml) at refluxfor 1 h. On cooling to 0°, the resulting precipitate was collected anddried to give the desired material (3.38 g) as a white solid.

EXAMPLE 18N[3-(2-Diethylaminoethoxy)phenyl]-4-(3-methoxyphenylsulphanyl)-2-pyrimidineamine

To a solution of the compound of Example 7 (325 mg, 1.0 mmol) in DMF (15ml) was added 2-diethylaminoethyl chloride hydrochloride (189 mg, 1.1mmol) and caesium carbonate (717 mg, 2.2 mmol) and the resulting mixtureheated at 100° for 4 h. After this time the solvent was removed underreduced pressure to give a residue which was partitioned between CH₂ Cl₂(10 ml) and brine (2×100 ml). The organic phase was dried (MgSO₄) andevaporated under reduced pressure to give a residue which was subjectedto column chromatography (silica; 5% methanol in CH₂ Cl₂) to give acolourless gum. This was taken up in ethyl acetate (25 ml) into whichdry HCl gas was bubbled, and the resulting precipitate was collected anddried to give the title compound (113 mg) as a yellow powder, m.p.192-193°. δH (d⁶ DMSO) 10.72 (1H, br s), 9.84 (1H, br s), 8.19 (1H, d, J5.4 Hz), 7.47 (1H, t, J 8.2 Hz), 7.31-7.06 (7H, m), 6.59 (1H, d, J 8.0Hz), 6.37 (1H, d, J 5.4 Hz), 4.35-4.32 (2H, m), 3.78 (3H, s), 3.48-3.46(2H, m), 3.19-3.16 (4H, m) and 1.25 (6H, t, J 7.2 Hz).

The compounds of Examples 19 and 20 were prepared in a similar mannerusing potassium carbonate in place of caesium carbonate.

EXAMPLE 19N-4,5-Dimethoxy-3-(2-pyrrolidin-1-ylethoxy)phenyl]-4-(3-methoxyphenylsulphanyl)-2-pyrimdineamine

FromN-(3,4-dimethoxy-5-hydroxyphenyl)-4-(3-methoxyphenylsulphanyl)-2-pyrimidineamine(500 mg, 1.3 mmol), 1-(2-chloroethyl)pyrrolidine hydrochloride (276 mg,1.6 mmol) and potassium carbonate (591 mg, 4.2 mmol) to give the titlecompound (430 mg) as a yellow solid m.p. 120-121°. δH (d⁶ DMSO) 11.27(1H, br s), 9.68 (1H, s), 8.18 (1H, d, J 5.4 Hz), 7.46 (1H, t, J 8.2Hz), 7.23-7.18 (3H, m), 7.13 (1H, d, J 2.4 Hz), 7.11 (1H, d, J 2.4 Hz),6.21 (1H, d, J 5.4 Hz), 4.31-4.27 (2H, m), 3.78 (3H, s), 3.72 (3H, s),3.67 (3H, s), 3.63-3.56 (4H, m), 3.18-3.10 (2H, m), 2.08-2.01 (2H, m)and 1.98-1.90 (2H, m).

The pyrimidineamine starting material was prepared from Intermediate A(3.03 g, 12 mmol) and 5-amino-2,3-dimethoxyphenol (2.0 g, 11.8 mmol) ina similar procedure to Example 1 to give the desired product (1.0 g) asan off-white solid m.p. 153-154°.

5-Amino-2,3-dimethoxyphenol was prepared by hydrogenation of a solutionof 1-benzyloxy-2,3-dimethoxy-5-nitrobenzene (2.5 g, 8.2 mmol) in ethanol(45 ml) over 10% palladium on charcoal (20 mg) at 20 psi and roomtemperature for 6 h. The catalyst was removed by filtration through apad of Celite® washing thoroughly with methanol. The combined filtrateand washings were evaporated to give the desired product (1.3 g) as adark grey solid.

1-Benzyloxy-2,3-dimethoxy-5-nitrobenzene was prepared by the methoddescribed in International Patent Specification No. W097/19065.

EXAMPLE 204-(3-Methoxyphenylsulphanyl)-N-{4-methoxy-[3-(2-pyrrolidin-1-yl)ethoxy]phenyl}2-pyrimidineamine

From the compound of Example 9 (502 mg, 1.28 mmol),1-(2-chloroethyl)pyrrolidine hydrochloride (262 mg, 1.54 mmol) andpotassium carbonate (575 mg, 4.1 mmol) to give the title compound (135mg) as a buff solid m.p. 147-149°. δH (d⁶ DMSO) 10.98 (1H, br s), 9.58(1H, br s), 8.15 (1H, d, J 5.5 Hz), 7.45 (1H, m), 7.30 (1H, m),7.18-7.16 (5H, m), 6.82 (1H, br s), 6.30 (1H, d, J 5.5 Hz), 4.25 (2H, brs), 3.77 (3H, s), 3.74 (3H, s), 3.56 (4H, br m) 3.12 (2H, m) and2.00-1.82 (4H, m).

EXAMPLE 21N-{3,5-Dimethoxy-4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}-4-(3-methoxyphenylsulphanyl)-2-pyrimidineaminedihydrochloride

To a solution ofN-{3,5-dimethoxy-4-[2-(p-toluenesulphonyloxy)ethoxy]-phenyl}-4-(3-methoxyphenylsulphanyl)-2-pyrimidineamine(1.0 g, 1.76 mmol) in DMF (6 ml) was added pyrrolidine (2.9 ml) and thereaction heated at 70° for 2 h. After this time the solvent was removedunder reduced pressure and the residue partitioned between ethyl acetate(100 ml) and saturated aqueous Na₂ CO₃ (10 ml). The organic phase wasdried (MgSO₄), concentrated under reduced pressure and the residuesubjected to column chromatography (silica gel; 12% methanol-CH₂ Cl₂).The resulting material was taken up in ethyl acetate and treated withhydrogen chloride gas to give a precipitate which was collected byfiltration and dried to give the title compound (440 mg) as a yellowsolid. δH (d⁶ DMSO) 10.67 (1H, br s), 9.72 (1H, s), 8.19 (1H, d, J 5.5Hz), 7.45 (1H, t, J 8.1 Hz), 7.22 (2H, m), 7.16-7.11 (3H, m), 6.23 (1H,d, J 5.5 Hz), 4.12-4.08 (2H, m), 3.77 (3H, s), 3.73 (6H,s), 3.69-3.62(2H, m), 3.47-3.42 (2H, m), 3.20-3.10 (2H, m) and 2.05-1.93 (4H, m).

The tosylate used as starting material was prepared by treating asolution ofN-[3,5-dimethoxy-4-(2-hydroxyethoxy)phenyl]-4-(3-methoxyphenylsulphanyl)-2-pyrimidineamine(2.0 g, 4.3 mmol) in pyridine (6 ml) with p-toluenesulphonyl chloride(3.28 g, 17.2 mmol) at room temperature for 2 h. Water (25 ml) was addedto the reaction followed by acidification with 2M hydrochloric acid, andthis was extracted with ethyl acetate (100 ml). The organic phase waswashed with 2M hydrochloric acid (100 ml) and saturated aqueous Na₂ CO₃(100 ml), dried (MgSO₄) and concentrated under reduced pressure to givethe desired product as a light brown oil (2.31 g). δH (CDCl₃) 8.04 (1H,d, J 5.4 Hz), 7.80 (2H, d, J 8.3 Hz), 7.39-7.30 (3H, s), 7.20-7.13 (2H,m), 7.03-6.99 (2H, m), 6.86 (2H, s), 6.22 (1H, d, J 5.4 Hz), 4.31 (2H,t, J 5.6 Hz), 4.13 (2H, t, J 5.6 Hz), 3.81 (3H, s), 3.77 (6H, s) and2.43 (3H, s).

The hydroxyethoxy starting material was prepared from Intermediate A(2.27 g, 9.0 mmol) and 4-(2-hydroxyethoxy)-3,5-dimethoxyaniline (1.92 g,9.0 mmol) using a similar method to the compound of Example 4 to givethe title compound as a yellow solid (2.4 g) m.p. 173-179°.

EXAMPLE 224-(3-Methoxyphenylsulphanyl)-N-{4-[N'-(2-pyrrolidin-1-yl)ethylcarboxamido]phenyl}-2-pyrimidineamine

To a solution of the compound of Example 8 (1.0 g, 2.56 mmol) in dry DMF(10 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (541 mg,2.82 mmol), hydroxyazabenzotriazole (383 mg, 2.82 mmol) andN-methylmorpholine (1.24 ml, 11.29 mmol) followed by1-(2-aminoethyl)pyrrolidine (0.36 ml, 2.8.2 mmol) and the reactionstirred at room temperature for 4 h. After this time the reaction wasconcentrated under reduced pressure to give a yellow oil which waspartitioned between brine (250 ml) and CH₂ Cl₂ (250 ml). The organicphase was dried (MgSO₄) and evaporated to a sticky white solid which wastaken up in hot ethyl acetate. The resulting solution was cooled,diluted carefully with hexane and the resulting precipitate collectedand dried to give the title compound (620 mg) as a white solid m.p.146-147°. δH (d⁶ DMSO) 9.92 (1H, br s), 8.39 (1H, br s), 8.23 (1H, d, J5.3 Hz), 7.70-7.67 (2H, m), 7.60-7.57 (2H, m), 7.49 (1H, t, J 7.2 Hz),7.24 (3H, m), 6.48 (1H, d, J 5.3 Hz), 3.79 (3H, s), 3.48 (2H, m),2.90-2.81 (6H, m) and 1.83-1.76 (4H, m).

EXAMPLE 234-(3-Methoxyphenylsulphanyl)-N-[3-(2-pyrrolidin-1-yl)ethyl]-2-pyrimidineaminedihydrochloride

From4-(3-methoxyphenylsulphanyl)--N-[3-(2-p-toluenesulphonyloxyethyl)phenyl]-2-pyrimidineamine(110 g) and pyrrolidine (5.1 ml, 62 mmol) in a manner analogous to thepreparation of the compound of Example 21, to give the title compound(450 mg) as a yellow solid m.p. 136-137°.

The tosylate starting material was prepared in a similar manner to theanalogous intermediate of Example 21, from the compound of Example 10(1.10 g, 3.1 mmol) and p-toluenesulphonyl chloride (2.36 g, 12.4 mmol)to give the desired compound (1.10 g) as a yellow oil which was usedwithout purification.

EXAMPLE 24N-{3-[2-(Pyrrolidin-1-yl)ethoxy]phenyl}-4-(3-methoxyphenylsulphanyl)-2-pyrimidineaminedihydrochloride

From the compound of Example 11 (1.0 g, 2.3 mmol), 1-(2-chloroethyl)pyrrolidine hydrochloride (476 mg, 2.8 mmol) and potassium carbonate(780 mg, 5.6 mmol) using the method of Example 18 to give the titlecompound (320 mg) as an off-white solid m.p. 199-200°. δH (d⁶ DMSO)11.04 (1H, br s), 10.08 (1H, s), 8.25 (1H, d, J 5.4 Hz), 7.78 (1H, s),7.71 (1H, s), 7.47 (1H, t, J 8.2 Hz), 7.24-7.21 (2H, m), 7.16-7.13 (1H,m), 6.90 (1H, s), 6.28 (1H, d, J 5.5 Hz), 4.82 (1H, br s), 4.40 (2H, m),3.78 (3H, s), 3.60-3.55 (4H, m), 3.14-3.08 (2H, br m) and 2.08-1.90 (4H,br m).

EXAMPLE 254-(3-Methoxyphenylsulphanyl)-N-(3-pyrrolidin-1-ylmethyl)phenylpyrimidine-2-amine dihydrochloride

To a suspension of the compound of Example 12 (465 mg, 1.24 mmol) inCHCl₃ (40 ml) was added thionyl chloride (0.3 ml, 1.36 mmol) and theresulting mixture heated at 55° for 6 h. The reaction was then dilutedwith CH₂ Cl₂ (60 ml), washed with saturated aqueous NaHCO₃, dried(MgSO₄) and concentrated in vacuo to a yellow oil. This residue wasdissolved in acetonitrile (25 ml), pyrrolidine (0.52 ml, 6.2 mmol) addedand the solution heated at reflux for 0.5 h. The reaction wasconcentrated in vacuo and the residue was subjected to columnchromatography (silica gel; 10% methanol in CH₂ Cl₂). The resultingmaterial was dissolved in an ethyl acetate/ethanol (1:10 v/v) mixture(10 ml) and treated with 1M hydrogen chloride in diethyl ether (2 ml).The precipitate which formed was collected and dried to give the titlecompound (300 mg) as a yellow solid m.p. 115-116°. δH (d⁶ DMSO) 11.17(1H, br s), 9.96 (1H, s), 8.21 (1H, d, J 5.4 Hz), 7.63-7.44 (3H, m),7.29-7.15 (7H, m), 6.43 (1H, d, J 5.4 Hz), 4.21 (2H, d, J 5.6 Hz), 3.78(3H, s0<3.90-3.80 (2H, br m), 3.05-2.94 (2H, br m) and 2.00-1.88 (4H, brm).

EXAMPLE 26N-(3-Aminophenyl)-4-(3-bromophenylsulphanyl)-2-pyrimidineamine

The compound of Example 15 (3.0 g, 6.82 mmol) was dissolved in ethanol(50 ml) and tin (II) chloride dihydrate (4.62 g, 20.47 mmol) added. Thereaction was heated at reflux for 3 h, after which time 2M aqueous NaOH(100 ml) was added and the resulting suspension extracted with ethylacetate (200 ml). The organic phase was dried (MgSO₄) and evaporated togive the title compound (2.1 g) as a pale orange solid m.p. 109-110°. δH(CDCl₃) 8.07 (1H, d, J 5.3 Hz), 7.79 (1H, s), 7.61 (1H, d, J 8.0 Hz),7.55 (1H, d, J 7.7 Hz), 7.33 (1H, t, J 7.9 Hz), 7.08 (1H, br s), 6.98(1H, t, J 8.0 Hz), 6.87 (1H, s), 6.68 (1H, d, J 7.0 Hz), 6.37-6.31 (2H,m) and 3.59 (2H, br s).

EXAMPLE 27N-{[4,5-Dimethoxy-3-(2-pyrrolin-1-yl)ethoxy]phenyl)-4-(4-fluorophenylsulphanyl)pyrimidine-2-amine dihydrochloride

In a manner analogous to the preparation of the compound of Example 21fromN-{4,5-dimethoxy-3-(2-p-toluenesulphonyloxy)ethoxy]phenyl}-4-(4-fluorophenylsulphanyl)pyrimidine-2-amine(1.3 g) and pyrrolidine (5.2 ml, 62 mmol) to give the title compound(550 mg) as a yellow solid. δH (d⁶ DMSO) 9.57 (1H, s), 8.18 (1H, d, J5.4 Hz), 7.71 (2H, dd, J 8.8, 5.4 Hz), 7.39 (2H, t, J 8.8 Hz), 7.15 (2H,dd, J 18.6, 2.3 Hz), 6.17 (1H, d, J5.4 Hz), 4.29 (2H, m), 3.75 (2H,m),3.72 (3H, s), 3.66 (3H, s), 3.59 (4H, m), 3.14 (2H, m), 1.98 (2H, m) and1.89 (2H, m).

The tosylate used as starting material was prepared in a similar mannerto the analogous intermediate of Example 21 fromN-[4,5-dimethoxy-3-(2-hydroxyethoxy)phenyl]-4-(4-fluorophenylsulphanyl)pyrimidine-2-amine(1.3 g, 3.12 mmol) and p-toluenesulphonyl chloride (1.78 g, 9.35 mmol)to give the desired compound as a light yellow oil which was usedwithout purification.

N-[4,5-Dimethoxy-3-(2-hydroxyethoxy)phenyl]-4-(4-fluorophenylsulphanyl)pyrimidine-2-aminewas prepared by treating a solution ofN-(4,5-dimethoxy-3-hydroxyphenyl)-4-(4-fluorophenylsulphanyl)-2-pyrimidineamine(2.23 g, 60 mmol) and ethyl carbonate (0.79 g, 90 mmol) in dry DMF (25ml) with potassium carbonate (1.66 h, 120 mmol) and heating theresulting mixture at 100° for 16 h. The reaction was concentrated underreduced pressure and the residue partitioned between ethly acetate andwater. The aqueous layer was re-extracted with ethyl acetate, thecombined organic layers dried (MgSO₄) and evaporated to give a residuewhich was subjected to column chromatography [silica; 20% hexane-ethylacetate] to give the desired compound (1.36 g) as a white foam. δH (d⁶DMSO) 9.48 (1H, s), 8.17 (1H, d, J 5.3 Hz), 7.69 (2H, m), 7.36 (2H, t, J8.8 Hz), 7.08 (2H, m), 6.15 (1H, d, J 5.3 Hz), 4.81 (1H, t, J 5.2 Hz),3.92 (2H, t, J 5.2 Hz), 3.73 (2H, m), 3.71 (3H, s) and 3.64 (3H, s).

EXAMPLE 284-(3-Bromophenylsulphanyl)-N-[4,5-dimethoxy-3-(2-pyrrolidin-1-ylethoxy)phenyl]-2-pyrimidineaminedihydrochloride

In a manner analogous to the preparation of the compound of Example 21from4-(3-bromophenylsulphanyl)-N-[4,5-dimethoxy-3-(2-p-toluenesulphonyloxyethoxy)phenyl]-2-pyrimidine-amine(2.16 g) and pyrrolidine (6.2 ml, 75 mmol) to give the title compound(680 mg) as a yellow solid m.p. 154-155°. δH (CDCl₃) 12.0 (1H, br s),8.25 (1H, br s), 8.03 (1H, d, J 5.7 Hz), 7.73-7.72 (1H, m), 7.62-7.59(1H, m), 7.53-7.50 (1H, m), 7.33 (1H, t, J 7.9 Hz), 6.87 (2H, s), 6.29(1H, d, J 5.7 Hz), 4.53-4.47 (2H, br m), 3.90-3.80 (2H, br m), 3.79 (3H,s), 3.77 (3H, s), 3.49-3.42 (2H, br s), 3.08-3.00 (2H, br m), 2.25-2.10(4H, br m).

The tosylate used as starting material was prepared from4-(3-bromophenylsulphanyl)-N-[4,5-dimethoxy-3-(2-hydroxyethoxy)phenyl]3-(2-pyrimidineamine (1.80 g, 3.76 mmol) and p-toluenesulphonyl chloride (2.16 g, 11.3mmol) in a manner similar to the analogous intermediate of Example 21and was used without purification.

4-(3-Bromophenylsulphanyl)-N-[4,5-dimethoxy-3-(2-hydroxyethoxyphenyl)-2-pyrimidineaminewas prepared in a manner similar to the intermediate of Example 19 as abuff solid. m.p. 151-152°. δH (CDCl₃) 8.07 (1H, d, J 5.4 Hz), 7.75 (1H,t, J 1.8 Hz), 7.61-7.50 (2H, m), 7.31 (1H, t, J 2.4 Hz), 7.17 (1H, brs), 6.87 (1H, d, J 2.4 Hz), 6.86 (1H, d, J 24.4 Hz), 6.25 (1H, d, J 5.4Hz), 4.08-4.05 (2H, m), 3.91-3.88 (2H, m), 3.81 (3H, s), 3.80 (3H, s)and 2.70 (1H, br s).

EXAMPLE 294-(3-Bromophenylsulphanyl)-N-[3-(N'-(S)-1-tert-butoxycarbonylprolyl)aminophenyl]-2-pyrimdineamine

In a manner similar to the preparation of the compound of Example 22,from the compound of Example 26 (1.0 g, 2.68 mmol),1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (514 mg, 2.68 mmol),hydroxyazabenzotriazole (402 mg, 2.95 mmol) N-methylmorpholine (0.88ml,m 8.04 mmol) and N-tert-butoxycarbonyl)-L-proline (635 mg, 2.95 mmol)to give the title compound (1.34 g) as a white solid m.p. 135-137°. δH(CDCl₃) 9.40 (1H, br s), 8.08 (1H, d, J 5.4 Hz), 7.77 (1H, t, J 1.8 Hz),7.64-7.60 (2H, m), 7.56-7.52 (1H, m), 7.35-7.22 (3H, m), 7.11-7.09 (2H,m), 6.37 (1H, d, J 5.4 Hz), 4.43 (1H, br s), 3.42 (2H, br s), 2.50 (1H,s), 2.00 (3H, br s) and 1.53 (9H, s).

EXAMPLE 304-(3-Bromophenylsulphanyl)-N-[3-(N'-(S)-prolyl)aminophenyl]-2-pyrimidineaminedihydrochloride

The compound of Example 29 (1.16, 2.02 mmol) was dissolved in ethylacetate (100 ml) and dry hydrogen chloride gas was bubbled into thesolution. After 10 min a precipitate appeared which was collected anddried to give the title compound (890 mg) as a yellow solid m.p. >175°(decomp). δH (d⁶ DMSO) 10.73 (1H, s), 10.17 (1H, br m), 9.91 (1H, s),8.64 (1H, br m), 8.22 (1H, d, J 5.4 Hz), 7.87 (1H, t, J 1.8 Hz),7.81-7.77 (2H, m), 7.68-7.66 (1H, m), 7.50 (1H, t, J 7.9 Hz), 7.26-7.23(2H, m), 7.07 (1H, t, J 8.1 Hz), 6.49 (1H, d, J 5.4 Hz), 6.07 (3H, brs), 4.40-4.37 (1H, br m), 3.30-3.20 (2H, br m, 2.43-2.38 (1H, m) and1.97-1.86 (3H, br m).

EXAMPLE 31N-{3,5-Dichloro-4-[(2-pyrrolidin-1-yl)ethoxy]phenyl}-4-(3,5-dimethylphenylsulphanyl)-2-pyrimidineamine

To a solution ofN-(3,5-dichloro-4-hydroxyphenyl)-4-(3,5-dimethylphenylsulphanyl)-2-pyrimidineamine(1.0 g, 2.55 mmol--prepared from 4-amino-2,6-dichlorophenol and2-chloro-4-(3,5-dimethylphenylsulphanyl)-pyrimidine according to themethod of Example 4) in dry tetrahydrofuran were addedtriphenylphosphine (802 mg, 3.06 mmol) and N-(2-hydroxyethyl)pyrrolidine(0.3 ml, 2.55 mmol), followed by diethyl azadicarboxylate (0.49 ml, 3.1mmol). The resulting solution was heated at reflux for 18 h and oncooling the reaction was partitioned between ethyl acetate (200 ml) andsaturated aqueous NaHCO₃ (200 ml). The organic phase was dried (MgSO₄),evaporated and the residue columned (silica;ethyl acetate) to give thetitle compound (400 mg) as a white foam. δH 8.08 (1H, d, J 5.8 Hz), 7.5692H, s), 7.17 (2H, s), 7.09 (1H, s), 7.05 (1H, s), 6.28 (1H, d, J 5.8Hz), 4.18 (2H, t, J 8.6 Hz), 2.59 (2H, t, J 8.6 Hz), 2.59 (2H, t, J 8.6Hz), 2.69 (4H, m), 2.31 (6H, s) and 1.80 (4H, m). MS m/z 489.2/490.9(MH+).

Biological Activity

The following assays were used to demonstrate the activity andselectivity of compounds according to the invention.

The activity of the compounds against src-family protein kinases can bedetermined in the following two assays:

p56^(lck) kinase assay

The tyrosine kinase activity of p56^(lck) was determined using a RR-srcpeptide (RRLIEDNEYTARG) and [γ-³³ P]ATP as substrates. Quantitation ofthe ³³ P-phosphorylated peptide formed by the action of p56^(lck) wasachieved using an adaption of the method of Geissler et al (J. Biol.Chem. (1990) 265, 22255-22261).

All assays were performed in 20 mM HEPES pH 7.5 containing 10 mM MgCl₂,10 mM MnCl₂, 0.05% Brij, 1 μM ATP (0.5 μCi[γ-³³ P]ATP) and 0.8 mg/mlRR-src. Inhibitors in dimethylsulphoxide (DMSO) were added such that thefinal concentration of DMSO did not exceed 1%, and enzyme [human p₅₆^(lck) ] such that the consumption of ATP was less than 10%. Afterincubation at 30° C. for 15 min, the reaction was terminated by theaddition of one-third volume of stop reagent (0.25 mM EDTA and 33 mM ATPin dH₂ O). A 15 μl aliquot was removed, spotted onto a P-30 filtermat(Wallac, Milton Keynes, UK), and washed sequentially with 1% acetic acidand dH₂ O to remove ATP. The bound ³³ P-RR-src was quantitated byscintillation counting of the filtermat in a Betaplate scintillationcounter (Wallac, Milton Keynes, UK) after addition of Meltilexscintillant (Wallac, Milton Keynes, UK). The dpm obtained, beingdirectly proportional to the amount of ³³ P-RR-src produced byp56^(lck), were used to determine the IC₅₀ for each compound.

In this assay the most potent compounds according to the invention haveIC₅₀ values of 100 nM or less.

p59^(fyn) kinase assay

Compounds of the invention were assayed for p59^(fyn) inhibitoryactivity in a similar manner to the p56lck assay, using human p59^(fyn).

The selectivity of compounds according to the invention can bedetermined in an assay utilising a serine/threonine kinase:

Protein kinase C assay

Inhibitor activity against protein kinase C (PKC) was determined usingPKC obtained from Sigma Chemical Company (Poole, UK) and a commerciallyavailable assay system (Amersham International plc, Little Chalfont,UK). Briefly, PKC catalyses the transfer of the γ-phosphate (³² P) ofATP to the threonine group on a peptide specific for PKC. Phosphorylatedpeptide is bound go phosphocellulse paper, subsequently quantified byscintillation counting and IC₅₀ values determined as described above.

In this assay, compounds according to the invention have IC₅₀ values of1 μM and above.

We claim:
 1. A compound which is selected from the group consistingof:4-(3-methoxyphenylsulphanyl)-N-{[3,5-dimethyl-4-(2-pyrrolidin-1-yl)-ethoxy]phenyl}-2-pyrimidineamine;4-(3-Carboxyphenylsulphanyl)-N-{[3,5-dimethyl-4-(2-pyrrolidin-1-yl)ethoxy]phenyl}-2-pyrimidineamine;N-[4,5-Dimethoxy-3-(2-pyrrolidin-1-ylethoxy)phenyl]-4-(3-methoxyphenyl-sulphanyl)-2-pyrimdineamine;4-(3-Methoxyphenylsulphanyl)-N-{[4-methoxy-[3-(2-pyrrolidin-1-yl)ethoxy]phenyl}-2-pyrimidineamine;N-{3,5-Dimethoxy-4-[2-pyrrolidin-1-yl)ethoxy]phenyl}-4-(3-methoxyphenyl-sulphanyl)-2-pyrimdineamine;N-{[4,5-Dimethoxy-3-(2-pyrrolidin-1-yl)ethoxy]phenyl}-4-(4-fluorophenyl-sulphanyl)pyrimidine-2-amine;4-(3-Bromophenylsulphanyl)-N-[4,5-dimethoxy-3-(2-pyrrolidin-1-ylethoxy]phenyl]-2-pyrimidineamine;N-{3,5-Dichloro-4-[2-pyrrolidin-1-yl)ethoxy]phenyl}-4-(3,5-dimethylphenyl-sulphanyl)-2-pyrimdineamine;and the salts and hydrates thereof.
 2. A compound according to claim 1which is4-(3-methoxyphenyl-sulphanyl)-N-{[3,5-dimethyl-4-(2-pyrrolidin-1-yl)ethoxy]phenyl}-2-pyrimidineamine;and the salts and hydrates thereof.
 3. A compound according to claim 1which is4-(3-carboxyphenyl-sulphanyl)-N-{[3,5-dimethyl-4-(2-pyrrolidin-1-yl)ethoxy]phenyl}-2-pyrimidineamine;and the salts and hydrates thereof.
 4. A compound according to claim 1which isN-[4,5-dimethoxy-3-(2-pyrrolidin-1-ylethoxy)phenyl]-4-(3-methoxyphenyl-sulphanyl)-2-pyrimdineamine;and the salts and hydrates thereof.
 5. A compound according to claim 1which is4-(3-methoxyphenyl-sulphanyl)-N-{[4-methoxy-[3-(2-pyrrolidin-1-yl)ethoxy]phenyl}-2-pyrimidineamine;and the salts and hydrates thereof.
 6. A compound according to claim 1which isN-{3,5-dimethoxy-4-[2-pyrrolidin-1-yl)ethoxy]phenyl}-4-(3-methoxyphenyl-sulphanyl)-2-pyrimdineamine;and the salts and hydrates thereof.
 7. A compound according to claim 1which isN-{[4,5-dimethoxy-3-(2-pyrrolidin-1-yl)ethoxy]phenyl}-4-(4-fluorophenyl-sulphanyl)pyrimidine-2-amine;and the salts and hydrates thereof.
 8. A compound according to claim 1which is4-(3-bromophenylsulphanyl)-N-[4,5-dimethoxy-3-(2-pyrrolidin-1-yl-ethoxy]phenyl]-2-pyrimidineamine;and the salts and hydrates thereof.
 9. A compound according to claim 1which isN-{3,5-dichloro-4-[2-pyrrolidin-1-yl)ethoxy]phenyl}-4-(3,5-dimethylphenyl-sulphanyl)-2-pyrimdineamine;and the salts and hydrates thereof.
 10. A pharmaceutical compositioncomprising, in combination with one or more pharmaceutically acceptablecarriers, excipients or diluents, an effective amount of a compoundaccording to claim 1.